JAMA  16 May 2012  Vol 307
Do we all live on the same planet? I’m nearing the end of an amazing year at Yale, surrounded by superlatively intelligent people working on the outcomes of US healthcare. I myself occupy a space with brilliant newly qualified young doctors from India, Iran, and Brazil, putting together a book on patient-centred medicine. Most of the ideas we discuss about patient autonomy and shared decision making are quite new to them. All day long we work in cyberspace with people all over the world. When we leave the confines of our artificially lit space with temperamental air-conditioning, we blink in the sunshine and walk past black garbage-sifters begging for money, sallow drug addicts, and drunk disabled people shouting at each other. We share a street with these people, a town, a country, a world. But I cannot say that we really share anything with them, except perhaps for some coins we have in our pockets.

Which brings me to this JAMA issue devoted to global health.

2031   It begins, as it should, with an essay on Primary Health Care in Low-Income Countries: Building on Recent Achievements. This is a great piece: terse, comprehensive, and optimistic. It begins: “Small investments in improved health of the poor have a remarkable return in reduced morbidity and mortality. While the developed economies grapple with health systems that cost several thousand dollars per person per year…outlays of just a few dozen dollars per person per year in impoverished countries can add several years to life expectancy.” This is one of the reasons—together with the BMJ UK-India piece by Rao and Mant—that I put out this tweet:

“RCGP shd get trainees to spend extra year not in pampered UK but in xchanges to build 1ry care in India, China, Africa.”

2039   And to bring the issues really alive, read this narrative about the Lifeline Express by an Indian medical student: A Train of Hope, and a Chance to Train.

NEJM  17 May 2012  Vol 366
1859   Here’s a big international study to settle the question of whether warfarin or aspirin is better at preventing stroke and mortality in heart failure with sinus rhythm. Well, that’s what the title would have you believe. In fact this is a truly old-fashioned study which defines “heart failure” by an ejection fraction under 35 and so ends up with a cohort of patients of mean age 61 and 80% male. It tells you nothing at all about your average patients with clinical heart failure who have a mean age of 76 and are 50+% female, half with normal ejection fractions. Their chances of going into atrial fibrillation and throwing off clots are much higher than those of this cohort. Someone needs to do a trial comparing a fixed-dose new generation anticoagulant with aspirin in this “real world” population.

1870   Progressive multifocal leukoencephalopathy (PML) is a ghastly fatal disease caused by activation of the JC virus, most frequently seen after the use of natalizumab in the treatment of multiple sclerosis. Natalizumab is a humanised monoclonal antibody against the cellular adhesion molecule α4-integrin, and it seems that it has the property of converting this common and normally harmless virus into an aggressive CNS pathogen. It is also among the more effective of recent treatments for relapsing-remitting MS. In this study, the manufacturers of natalizumab combine different sources of observational data to conclude that the absence of anti-JC antibodies before the use of this drug may predict an extremely low risk for the later development of PML.

1881    This study about the increased risk of cardiovascular death while taking azithromycin has got a lot of publicity. The increase in CV death for the average adult population is put 47 per million taking a five day course of this antibiotic rather than amoxicillin: it is considerably higher in those at increased CV risk, of course. But there is an easy way to remember not to give this or any other macrolide antibiotic to those at highest risk: just heed your computer warning that all these drugs interact with statins.

1891   The paper that got the most publicity in this week’s New England Journal though was this one showing that coffee consumption is associated with lower all-cause mortality. This seems dose-related too, which is good news as I sit here all a-buzz from a mug brewed to the strength my wife likes. Legend has it that coffee reached the West via the Turkish armies who were defeated at the walls of Vienna in 1683, complete with bread rolls in the shape of the Islamic crescent. Which is still the best—and now perhaps the healthiest—breakfast; and the surest mark of advanced civilization.

Lancet  19 May 2012  Vol 379
1879    And still they come: industry-funded trials of amazingly expensive drugs for incurable cancers. This week there are two in The Lancet: this one looks at pazopanib, a tyrosine kinase inhibitor made by GlaxoSmithKline and compared with placebo in 72 institutions, across 13 countries on patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma. The drug costs about £2.3K per month, and life in the pazopanib group was extended by 1.8 months, within a mean survival period of just over a year. Diarrhoea and fatigue were very common side-effects. I see from the BMJ that the UK has just been ranked 12th in the European league of 34 health systems, and that the study leader, Arne Björnberg, marked us down because our access to new cancer treatments is “deplorable.” But then some new cancer treatments, and the prices charged for them, are themselves best described as deplorable.

1887   An Oxford-based group called IDEAL was recently set up to improve the methodology of surgical trials: this RCT of minimally invasive versus open oesophagectomy for patients with oesophageal cancer nicely illustrates the problems. Learning curves; case selection; end-points; inter-centre differences; duration; power—to name but a few. Here the groups totalled 57 and 59 each: there were two in-hospital deaths in the minimally invasive group and one in the open group, but far more of the latter got post-operative pneumonia. We will have to wait for longer-term data.

1893   Here is the second GSK cancer drug trial—a phase 1 safety and dosing study of dabrafenib, an inhibitor of BRAF kinase that is selective for mutant BRAF. It is always a mistake to get excited by phase 1 trials, but this is a drug to watch: it shrinks away a whole range of solid metastatic tumours, even including metastases of melanoma in the brain, which should be beyond its reach. There were no discontinuations due to adverse events.

After flirting briefly with items in the online first sections of the journals, I’ve largely gone back to the weekly printed items, for the sake of simplicity. But two papers on The Lancet’s website this week cry out for comment, as they put the final nails in the “treat-to-target” lipid management coffin. I hope.

The first one is old news, but repackaged as a huge meta-analysis of individual patient data from 27 randomised trials of statins which included subjects at low risk of cardiovascular events. Guess what? Everybody’s risk came down, whatever it was to start with. And the mortality benefit of the statin therapy was directly in proportion to the fall in LDL-cholesterol, and it far outweighed any measurable harms. So should everybody take a statin, so as to reduce the population rate of CV disease? No, I object to this kind of public-health-speak: everyone who wants to should be able to: it’s a personal choice. And does this prove that statins work by LDL-C lowering? Again no. They just work, and people should take them or not, as they wish to adjust their life chances.

And now onto the question of “good” cholesterol—HDL-C. There is a linear relationship between this lipid fraction and a decrease in cardiovascular risk. So far, 200 or more trials have been done with HDL-C raising agents; and not one of them has succeeded. Roche has just terminated its trial of dalcetrapib for futility, leaving the Oxford CTSU trial of anacetrapib (REVEAL) about the only one left standing. I wonder if it will ever recruit its 30,000 subjects. Here a massive Mendelian randomisation study shows that the HDL-C/CV protection association is unlikely to be causal, and plasma measurements of HDL-C may actually tell us very little.

BMJ  19 May 2012  Vol 344
A study from the Highlands and islands of Scotland looks at mortality in men screened for abdominal aortic aneurysm. I was somewhat fazed to see this defined by an aortic diameter of 30mm or more: in the MASS study and in my clinical practice, the threshold was 55mm. But this is only a fairly crude associational study which unsurprisingly shows that the diameter of the aorta in old men is a marker for high cardiovascular risk and cancer risk, almost all of it attributable to smoking.

Another observational study from the Hibernian regions looks at the outcomes of 1 271 549 bonnie lassies who produced wee bairns between 1981 and 2007. “At each gestation between 37 and 41 completed weeks, elective induction of labour was associated with a decreased odds of perinatal mortality compared with expectant management.” Nature is not a wise Mother. Human parturition is a chancy business, and it’s no wonder that by some estimates, the total population of Homo sapiens fell to 10,000 at one point before we learned to conquer stupid cruel Nature and take over the world.

Ann Intern Med  15 May 2012  Vol 156
673    Here’s how evidence-based medicine is supposed to work. We categorize a certain group of patients as having a condition in common: in this case it is chronic obstructive pulmonary disease. We conduct randomized controlled trials of interventions in a sufficiently large group of patients with the defining features of the condition, to determine what effect these have on important end-points which usually include death and hospitalization. Finally—and by no means always—we conduct further trials on methods of ensuring that these patients get the interventions which we have shown to be beneficial. A Comprehensive Care Management Program to Prevent Chronic Obstructive Pulmonary Disease Hospitalizations is an example of the final stage of EBM: implementation research. Comprehensive care management seems such a self-evidently good thing that it comes as little surprise that the study was terminated early. But the reason was that after a mean follow-up of 250 days, there had been three times as many deaths in the intervention group, and the same rate of hospitalizations. It seems to me that there could be two factors at work here. First, the interventions we encourage for COPD may be doing more harm than good, especially in the large number of patients with coexisting cardiovascular disease. Secondly, the effect of constantly reminding people of their disease status may be harmful in its own right—as demonstrated by the study which showed a fourfold mortality in sick elderly patients kept under close telemonitoring.

Arch Intern Med  16 May 2012
686     I am an avid eater of all kinds of fish, and I think my absolute favourite is a large fresh herring fried in butter. Unfortunately you probably have to live on the West Coast of Scotland to obtain such an article: away from fishing ports you are safest with kippers, as there is nothing worse than a stale herring. Eating is meant for sustenance and pleasure. It has also been found that eating a diet rich in fatty fish is associated with better cardiovascular health—and if there is any evidence against butter, I have yet to read it. Unfortunately a large proportion of mankind seems to be averse to eating the oilier species of fish, and instead, many seek to obtain CV benefits from omega-3 fatty acid supplements. But as this systematic review reveals, there is no evidence worth the name that these achieve anything for secondary prevention following cardiovascular events.

715    Several years ago I was intrigued to learn about the possibility of distinguishing between bacterial and non-bacterial infections using measurement of procalcitonin. But this is far more expensive in time and money that prescribing a course of antibiotics, and it has not caught on very widely. This observational study from primary care in Switzerland, France, and the USA shows that where it is used, antibiotic prescribing can fall markedly without affecting patient outcomes.

724   Finally, an insight into the bizarre world of American lipid prescribing: target-driven, irrational, and profoundly distorted by big pharma. Fenofibrate is a drug which has repeatedly been found to have no beneficial effects whatsoever, though it lowers “bad” lipids, including triglycerides. As evidence for its uselessness mounted, fenofibrate prescribing in the USA soared, driven by advertising from Abbott Laboratories. But this $1bn-a-year triumph of marketing over evidence was due to come to an end when Abbott’s patent expired. This paper describes how Abbott fought off the threat of generic competition and continues to sell modified fenofibrate products with rights to exclusivity. Its lead author is Nick Downing, a medical student with a unique accent forged in London and Harvard, whom I met when he first began work on this at the end of his first year as a medical student at Yale last year. Well done Nick! But hang on—what is this I see on the NEJM website? A full special report on regulatory agencies in the US, Europe, and Canada, with first author Nicholas Downing. For a second-year medical student to publish one paper in a leading medical journal might be called good fortune; to publish two begins to look like brilliance.

And do read this inspiring advice to Be Brave, from Nick’s mentor Harlan Krumholz.

Plant of the Week: Paulownia tomentosa

This delightful tree has vast leaves and wonderful panicles of scented blue foxglove flowers at this time of the year. It comes from China where it was discovered in the mid-nineteenth century and named for a Russian princess Pavlovna, who had moved to the Netherlands and was known there as Anna Paulowna. She would be forgotten now, but for this botanical tribute, being a mis-spelt version of her name with the Latin word for “hairy” added on. Perhaps the poor lady was not very popular in her new homeland.

Certainly the tree itself does not thrive in damp northern maritime climates. But I was astonished to see numerous paulownias in full flower on a recent rail journey into New York City. Wikipedia tells the story of how they came there:

In China, an old custom is to plant an Empress Tree when a baby girl is born. The fast-growing tree matures when she does. When she is eligible for marriage the tree is cut down and carved into wooden articles for her dowry. Carving the wood of Paulownia is an art form in Japan and China. In legend, it is said that the Phoenix will only land on the Empress Tree and only when a good ruler is in power. Several Asian string instruments are made from P. tomentosa, including the Japanese koto and Korean gayageum zithers.

The soft, lightweight seeds were commonly used as a packing material by Chinese porcelain exporters in the 19th century, before the development of polystyrene packaging. Packing cases would often leak or burst open in transit and scatter the seeds along rail tracks. This, together with seeds released by specimens deliberately planted for ornament, has allowed the species to become an invasive weed tree in areas where the climate is suitable for its growth, notably Japan and the eastern United States.

JAMA  9 May 2012  Vol 307
1925    In a wonderful letter to Humphry Davy in 1800, Coleridge declared that science, as a human activity, “being necessarily performed with the Passion of hope, is poetical.”

All good science is inspired with the poetry of hope; but, alas, so also is a lot of bad science. If results are negative, then it is a lot easier to hope vainly that they contain hints of great things to come than to admit that years of effort have simply proved nullity.

And if a simple cheap intervention like intravenous glucose, insulin and potassium (GIK) seems to have promise in the treatment of acute myocardial infarction, all of us would much rather hope this is true than dismiss the possibility altogether.

Several randomised trials have proved that GIK makes no difference when given in hospital, so this double-blinded RCT investigates whether the same applies to GIK given by emergency service personnel to patients with presumed cardiac chest pain before arrival at hospital.

Again, there was no 30-day mortality benefit; but since (as a poet before Coleridge said) hope springs eternal in the human breast, the investigators draw attention to the fact that GIK was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality. Nah, that won’t quite do: when I have a myocardial infarct, I want to be alive at 30 days. This intervention is beyond hope: GIK RIP.

1959    Back to the world of hope, this time that probiotics will prevent antibiotic-associated diarrhoea. Again, a nice idea that costs next to nothing and has a certain mechanistic appeal: it’s just that when you do a systematic review of the evidence, it is all over the place.

By all means continue to hope that eating a daily pot of live yoghourt or drinking a concoction of lactobacilli will stop you running to the loo when you next need an antibiotic: but in fact nobody really knows, as there have been too few decently powered trials.

NEJM  10 May 2012  Vol 366
1759   $163,381 per year for the average patient. That is the US cost for lenalidomide according to the website of its manufacturer, Celgene. Multiple myeloma is a nasty disease, and lenalidomide is now standard last-ditch treatment to prolong life following relapse: not a matter of hope but of evidence.

Drug companies that charge £10K a month for life-prolonging treatment generally justify this on the grounds that research and development costs can be huge and the returns are uncertain.

The Celgene-funded trial described here was certainly expensive: 459 patients with newly diagnosed myeloma who were unsuitable for stem-cell therapy were recruited from 82 centres in Europe, Australia and Israel; and Celgene did not stint in offering the services of its staff either: “Employees of the company assisted with the study design, data collection, data analysis, and writing of the manuscript in collaboration with the senior academic authors.”

At 30 months, there was better progression-free survival in the continuous lenalidomide group. Now that may be worth something, but whether it is worth $163,381 per annum will depend on more than progression-free survival at 30 months: so read on.

1770   The next trial of maintenance lenalidomide in this week’s NEJM was the same size, with 460 patients; but since it was not company-funded, it managed to recruit these from about 17 centres in a single country (the USA).

Celgene’s only contribution was to provide its drug or matching placebo free of charge to myeloma patients who had undergone stem-cell transplantation.

In this study, 85% of patients in the lenalidomide group and 77% of patients in the placebo group were alive at a median follow-up of nearly 3 years. But since the mean survival for MM treated with stem-cell transplantation is now 8 years, does this really amount to $163,381- per-annum’s worth of benefit?

Moreover, while the trial conducted and written up by Celgene plays down the adverse effects from lenalidomide, this trial illustrates the heavy preponderance of severe haematological adverse effects and secondary cancers in the lenalidomide group.

1782   Now to France, for a very similar study of lenalidomide maintenance following stem-cell transplantation.

Again, the immediate benefit in terms of progression free-survival seems impressive, until you consider that this is an intervention of spectacular cost with diminishing benefits and increasing serious harms over time: it is far from clear whether the whole cohort of 614 patients would show any overall survival benefit, and the lenalidomide group would certainly have 2-5 times as many secondary cancers over the 8+ years that studies like this should report for.

The linked editorial is worth reading by anyone who thinks $163,381 per annum is a rather a lot of money for maintenance therapy of uncertain long-term benefit.

1792   I have had a lot of exposure to US cardiovascular outcomes research over the last year, and very enjoyable and formative it has been. I’m left convinced that there is no particular hierarchy of research in this area: good observational studies can be of the highest value, and qualitative or mixed-methods research can yield much more of practical value than some clever exercise in endless statistical adjustment and regression applied to a large database.

Randomised controlled trials are relatively uncommon in this field, so while they do not automatically count as top dog, they are always interesting. Given that elective percutaneous intervention is now a procedure with very small immediate risks (e.g. acute MI, dissection of the coronary artery), PCI is often performed in hospitals without on-site cardiac surgery.

If this interests you deeply, you can read all about it in a review. This massive trial (n=18,867) randomised patients needing PCI on a 3:1 basis to hospitals with or without cardiac surgery units. Readers who object to the word noninferiority must clench their teeth at this point, because that is what this trial showed. And anyone who claims that this word does not belong in the English language will be sent a punitive stream of e-mails until they beg for mercy.

Lancet  12 May 2012  Vol 379

1763   Science for action-based nursing: a great addition to the treasury of Lancet headings, perfectly combining the meaningless and the pompous. This little piece bewails that fact that nurses have trouble basing their practice on evidence. Not like doctors, of course.

As for action-based nursing, that is the kind I like. Non-action-based nursing is the kind that ignores patients’ pleas for help getting up and going to the toilet, or the fact that their food tray is out of reach. There is plenty of that about, alas. It does not need science but basic humanity. And then there are the innumerable non-action nurses who have grown too senior to look after patients at all: what they need is not science but alternative employment.

1791   Non-inferiority: a great word. Though here it appears hyphenated, out of a British sense of propriety, and the trial fails to demonstrate it. Instead – and even better – it proves that one treatment for advanced Hodgkin’s disease is more successful than another, as well as involving fewer cycles and fewer adverse effects. We are taking here of BEACOPPescalated followed by PET-guided radiotherapy. Do I know what BEACOPPescalated  means? Of course not – read the paper yourself if you need to know.

1800   Pessary: a great word. If I didn’t know better, I would guess that it referred to a small land mammal related to the otter. Pessaries live socially in burrows containing several breeding pairs, and subsist on a mixed diet of roots, larvae and worms. Well, sadly (perhaps) not: the Pesario Cervical para Evitar Prematuridad (PECEP) Trial Group was, as its name suggests, more concerned to prevent premature delivery in gravid women with a short cervix. The pessaries are made of silicone and were inserted following ultrasonography showing a short cervix at 18-22 weeks. Although similar devices have been used for 50 years, this was the first randomised trial and it was highly successful, cutting the rate of delivery before 34 weeks more than fourfold.

BMJ  12 May 2012  Vol 344

That smoking cessation is a great good is undeniable, and varenicline undeniably helps many people to stop smoking.

Does it therefore follow that varenicline is a great good? This is a nice debating point, because smoking cessation is actually a surrogate end-point, albeit one directly linked with certain outcome benefits; yet these benefits can be outweighed by other considerations, such as direct cardiovascular harm from the intervention itself.

A previous meta-analysis seemed to show a 72% increase in risk of serious CV events from taking varenicline: this one shows no increase in risk. The main reason is ascertainment bias in the trials which had poor follow-up data from placebo groups; but the fact remains that we can never be full sure until the manufacturer releases full individual data from its trials for independent scrutiny, as should be mandatory in all cases like this.

Multidisciplinary care for breast cancer is a self-evidently good thing if it helps to support women through their traumatic disease journey. It is a self-evidently bad thing if it leaves nobody with overall responsibility and makes promises it cannot deliver – and that can happen too. These considerations apply whether or not it has a benefit on mortality. The chances are that it has, because in two adjacent areas of Scotland where it was introduced at different times, the rate of mortality fell more in the area which got it first. You can argue about the figures, but the principle is incontestable. Team care is here to stay – and we need to make sure it is as humane and well-coordinated as we can possibly make it.

A couple of weeks ago, I read with incredulity and nausea a statement called Guidance on collaboration between healthcare professionals and the pharmaceutical industry, produced by the Association of the British Pharmaceutical Industry and signed up to, inter alia, by the British Medical Association, of which I am a member. I don’t dare give the link in case it exposes me to derision by my American colleagues, because I don’t believe that even the AMA, with all its links to industry, could ever have put its name to something quite so disingenuous and servile. Anyway, thank God for Ray Moynihan, who gives it the once-over this week, ending splendidly:

“This latest guidance on collaboration is extremely welcome, not as a guide to practice, but as an Orwellian insight into a desperate attempt to defend the indefensible.”

Plant of the Week: Magnolia grandiflora

At this time of the year, I generally commend to your attention the wonderful Himalayan magnolia species with scented pendant flowers, M sinensis and M wilsonii. My wife forbids me to commend the American species M grandiflora because it looks gloomy all the year round in the UK: it flowers reluctantly in our warmer summers, and carries its large dark shiny leaves with a sort of morose persistence. I have to admit she is right, though we both forgive it everything when burying our noses in its huge beautiful white flowers with their intoxicating scent of spices, honey and lemon.

This we had ample opportunity to do while visiting its native habitat in Georgia – not the former Soviet state but the American colony set up by King George III of England to get rid of the London poor. In the South-East USA, the bull bay can become a huge tree, over 100ft in height and 18ft in circumference. Smaller cultivars abound in the parks of Atlanta and along the interstate highways, flowering generously by early May.

I am not saying that you should never grow this plant in England, especially if you have a warm wall to cover. But be prepared for a measure of disappointment, and make sure that you keep it publicly accessible, so that we can get to smell its flowers should they ever appear.

JAMA 25 Apr 2012 Vol 307
1809    Among the many virtues of JAMA, one cannot number a strong sense of the ridiculous. The poetry and medicine section is the world’s most reliable source of po-faced bad verse, this week’s example being an invective against Decadron; and the first research paper this week is a study called FISH.

This is short for Fish Oil Inhibition of Stenosis in Hemodialysis Grafts; and believe it or not, this is a study which aims at finding out whether a fish oil capsule produced by Ocean Nutrition Canada Ltd prevents stenosis in newly formed arteriovenous shunts in haemodialysis patients over a 12 month period. Or, as a typical JAMA poet would put it:

Dragged in shoals from the Canadian oceans, unwillingly their flapping silver bodies yield
Oils rich in omega-3 fatty acids with antiproliferative, antioxidant, and vasodilatory effects
Reeking with promise to keep open life-giving shunts in the renal unit.
Only they don’t.
Alas!

1817   For mere bystanders, the world of interventional cardiology never ceases to amaze with its profusion of trials seeking to compare one odd sounding intervention with another. The bottom line of this paper about the INFUSE-AMI is that intracoronary abciximab is superior to manual aspiration thrombectomy in patients with large anterior myocardial infarction.

I guess you have to be either an interventional cardiologist or a trial methodology dweeb to find this very interesting. Bear with me: I am becoming somewhat of the latter, and to me this looks like a complex marketing trial, and intrigues me like a rare fungus (you can skip to the next section at this point).

“Atrium Medical was involved in the design and conduct of the study and site selection and had the right to a nonbinding review of the manuscript.”

Atrium Medical makes coronary artery catheters for drug delivery, so they have a natural interest in promoting the use of intracoronary drug delivery. And one way to do that is to compare it with a technique that has already been shown to fail in the majority of trials – coronary clot aspiration. The thing not to do is compare it with intravenous abciximab delivery, because that might prove just as good.

It pains me to list all the other potential defects of this trial, but basically it had a 2×2 factorial design, was single blinded, enrolled only 7.2% of MI patients presenting at 37 sites in 6 countries, used an end-point (infarct size at 30 days) which was not accurately determined in a significant proportion of patients, with a difference in pooled groups of small statistical significance, plus four other disadvantages you can read about from the authors themselves in the comment section.

And by the standards of the trials which regularly appear in the top journals, it is not even particularly bad.

1838    When I was a GP in the prime of life, Muir Gray bade me read a book called Clinical Epidemiology written by a number of Canadians. Reading Sackett et al by day and by night, I suddenly became aware of the wonders of randomised controlled trials, the potential of the internet, the intellectual challenge of using diagnostic tests according to Bayesian principles, the need to seek evidence, evidence, evidence.

My heart still aches for the simple optimism of that vision. Instead, most of what we deal with in medicine is complexity made worse by inadequate knowledge. Surely the way forward must lie with further clinical trials.

These days, if you want the results of your trial to appear in a peer-reviewed journal, it has to be registered; and the US registry is known usefully as ClinicalTrials.gov. Here the past and present custodians of this site look at the quality of the trials registered between 2007 and 2010. They “are dominated by small trials and contain significant heterogeneity in methodological approaches, including reported use of randomisation, blinding, and data monitoring committees.”

In other words, these trials are never going to yield clinically dependable data; most of them are futile, and therefore by definition unethical. Something is terribly wrong with the system which governs clinical trials: it is failing to protect patients and failing to generate useful knowledge. Most of what it produces is not evidence, but rubbish. And with no system in place to compel full disclosure of the data, it is often impossible to tell one from the other.

NEJM  3 May 2012  Vol 366

1663   Now when we doctors seek certainty, the person we ask is the histopathologist. Thyroid cancer, however, is notoriously difficult to define, even under the microscope. Since a lot of it is actually benign, it is also difficult to know how to treat it. In this French study, they went for total thyroidectomy followed by the use of recombinant human TSH (thyrotropin) plus one of two doses of radioiodine (131I). The outcome measure was total thyroid ablation as assessed by neck ultrasound and TSH-stimulated thyroglobulin production. The lower dose of radioiodine (1.1GBq) proved as effective as the higher (3.7 GBq). By this short term measure, 95% of patients in the trial seem to have been cured.

1674   A very similar British trial using the same method of thyroid stimulation and the same doses of radioiodine produced cure rates which were slightly lower – 85-89%.

1686   The Placement of Aortic Transcatheter Valves (PARTNER) trial did what it says on the can: placed a lot of new aortic valves via a catheter (TAVR), so sparing patients the ordeal of open surgery. One part of the trial randomised patients at high risk of decompensation to one or other procedure, and at one year the two procedures yielded very similar results for mortality, symptoms and haemodynamic measures. This report gives the two-year results: there is now a divergence towards paravalvular regurgitation in the TAVR group which is associated with higher mortality.

1696   Another part of the PARTNER investigation randomised patients with inoperable decompensating aortic stenosis to either TAVR or standard management (which often included balloon valvuloplasty). In these unfit elderly patients (mean age 83) with severe heart failure (mostly NYHA III-IV) survival for 2 years was 56.7% in the TAVR group and 32% in the others. So worth a go in “appropriately selected patients”, as the usual phrase has it. The fittest survive the best, even at this level.

1705   And if you are a breathless 83-year-old with aortic stenosis, it may be best to go and have your TAVR procedure done in France. Here are some registry data from that country, fresh as a newly baked baguette -3195 patients enrolled between January 2010 and October 2011 at 34 centres, mean age 82.7. Rates of death at 30 days and 1 year were 9.7% and 24.0%, respectively. Formidable!

1716   The article that this issue of the NEJM will be best remembered for, however, is Atul Gawande’s wonderful Two Hundred Years of Surgery. The whole piece is open access so there is no need for me to quote extensively. My favourite bit is in parentheses half way through:

“Liston operated so fast that he once accidentally amputated an assistant’s fingers along with a patient’s leg, according to Hollingham. The patient and the assistant both died of sepsis, and a spectator reportedly died of shock, resulting in the only known procedure with a 300% mortality.”

Lancet  5 May 2012  Vol 379

1705   “Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial.”

Spartan Biosciences has developed a bedside test which allows rapid genotyping for the CYP2C19*2 allele. The simple story is that patients with this allele don’t respond to clopidogrel but do better with prasugrel, and that you can test this by measuring platelet reactivity, which was the outcome measure for this trial.

But the evidence from randomised trials of clopidogrel v prasugrel is a good deal less clear. Moreover, I can’t see why a bedside test is needed for patients who have just had percutaneous coronary intervention and are lying in a hospital bed close to a proper pathology laboratory. So the concept that this trial proves is that you can get a Lancet paper out of a genetic test that predicts a surrogate marker, immediately and expensively.

What it does not prove, thankfully, is the concept that the future of medicine lies in double rip-off – ripping off for the genetic test and then ripping off for the expensive drug.

1721   Although obstetrics led the rest of medicine in auditing its outcomes (and thanks to Iain Chalmers, in systematically reviewing its evidence base), a lot of obstetric practice remains based on tradition rather than evidence. Clamping of the cord is one example: controlled cord traction in the third stage is another.

This huge trial was designed to put the question to rest for ever, with nearly 12,000 women in each arm, randomized to active or expectant management. In the end, the trial fell victim to its own power: the results almost prove noninferiority for expectant management, but with so many subjects in the final count, a slight advantage for cord traction reaches statistical significance. The main message is to give oxytocin promptly if you want to avoid haemorrhage.

1739   In my youth it was an article of faith in the north of England that wearing glasses meant you were a swotty weakling, and I suffered deep chagrin when I acquired the nickname “Goggles” at the age of 9.

I know I didn’t acquire myopia from too much reading because I first got glasses at the age of 6: destiny had clearly determined at an early stage that I would be a swotty weakling with glasses and so I have proudly remained to this day.

The very idea that you could become myopic through too much close eye-work always struck me as fanciful, but this Lancet review points to a huge increase in myopia among school-leavers, especially in east Asia (80-90% prevalence). To dismiss the possibility that this is caused by reading, iPads, computers, and television, and lack of outdoor activity would definitely be short-sighted.

BMJ  5 May 2012  Vol 344

At the end of his essay on 200 years of surgery, Atul Gawande endearingly admits that he has no idea what “nanotechnology” means but predicts that it will have replaced surgery within 100 more years. Operations like appendicectomy will have vanished as minute robots or something do unknown things in ways we cannot yet predict.

Or do we already have enough evidence to relegate surgery for appendicitis to a second-line place in management? This systematic review of 4 studies makes the case for using antibiotics first: that way you may be able to avoid surgery in two-thirds of cases. I am not wholly convinced, but this is certainly a debate to watch.

Another surgical debate to watch will be the aftermath of the metal-on-metal hip debacle. This study comparing hip resurfacing with total arthroplasty is already obsolete: it was a randomized trial, the first of its kind, but the resurfacing was all metal-on-metal, and so now banned due to long-term harms. For the record, the two procedures had identical outcomes at one year.

Ann Intern Med  1 May 2012  Vol 156

618    Here’s a study of hospital atrategies for reducing risk-standardised mortality rates in acute myocardial infarction: an impeccable paper about an important topic, and moreover one which marries the insights of qualitative research with rigorous quantitative analysis of observational data.

Am I praising this too much? I don’t think so, though I have to confess that I’ve been working for the best part of a year among the team that produced it. I thought they were incomparable before, and now I know it for a certainty.

So call me biased, but do read this paper: it shows that virtuous care is rewarded, but sadly not by very much. Standardised MI mortality in the 537 US hospitals examined varies by about 10% in a near-normal distribution, but only just over 1% can be accounted for by the factors which emerged from qualitative interviewing of hospital staff: a culture that encouraged physicians to solve problems creatively, physicians and nurses, acting as quality-of-care champions, hospital and emergency department clinicians meeting at least monthly to review care, cardiologists always being present in the hospital, and not cross-training nurses to work in both intensive care and cardiac catheterization settings.

Fungus of the Week: Pleurotus eryngii

I had hoped that spring in New Haven would bring large crops of morels on the flowerbeds of Yale, which are all heavily mulched with shredded bark, a favourite substrate for these delicate fungi. But the only place I ever saw any was in a delicatessen, at $69.99 per pound. The same deli also offers Pleurotus eryngii at $19.99 per pound, while another Italian deli nearby charges $9.99 and a local Chinese supermarket has huge ones at $3.99.

These “king oyster mushrooms,” or whatever you want to call them, have a flavour highly reminiscent of the much-prized Boletus edulis. You are most unlikely ever to find them in the wild, even in their Mediterranean habitats. As organs of reproduction, they are singularly ill-adapted, having but a few ineffective gills high on an enormous fruiting body. But by the same token, they provide a lot of meat for those who eat them. They are very easy to cultivate, though I have seen them but rarely in British shops. In the peak of condition they are probably the finest of the cultivated mushrooms.

I think the best stage to buy them at is about 12cm long, still with a distinct though small brown cap. Larger ones can be a bit rubbery. You can eat them raw, thinly sliced with olive oil and shavings of parmesan. You can slice them more thickly and fry in butter with shallot, and decorate with parsley. Or in olive oil with garlic, à la bordelaise. You can put them in a pan with rashers of bacon and they will cook nicely together.

You can no doubt use them in most cep recipes, such as truite aux ceps, though I have not yet tried this. Worth seeking out.

JAMA  25 Apr 2012  Vol 307
1717   Any budding young cardiology academic wishing to set up a publication of her own could do worse than start a Journal of Negative Stem Cell Trials in Heart Failure. There are enough of these to fill a volume every quarter-year or so, and editorials could reflect on all sorts of fascinating issues to do with how to wash bone-marrow cells, whether to pre-treat them with this or that, which bit of myocardium to put them in, whether tiny differences in this or that functional measure in various aggregated subgroups indicated that this treatment might actually work one day, etc, etc. This would save the rest of us from having the disappointment of bumping into these papers on a regular basis in the main medical journals. Ten years ago, they were really exciting, and we all took heart, so to speak; but the FOCUS-CCTRN published here is just another failure like the rest. The cells were autologous bone marrow mononuclear cells; they were introduced by transendocardial injection, mostly into male hearts damaged by ischaemia, and at six months there was no evidence that they were doing anything to any of 8 outcome measures.

1727   About 6% of infective endocarditis is associated with implantable cardiac devices, and the vast majority of the culprits are pacemaker batteries. So although the wires are in the heart, the germs are on the subcutaneous box and reach the heart valves through the bloodstream. The treatment is to get the device out as soon as possible: these infections carry a substantial mortality which increases with delay in removal.

1736   Recurrent severe migraine is a blight on anyone’s life, for which there are a number of prophylactic drug treatments, none of them infallible, and many of them unsatisfactory. So a simple mechanical cure would be a great breakthrough, were it to exist. Botulinum toxin injections to the forehead muscles do alleviate some types of headache, as this meta-analysis shows, but the effect is modest and is only detectable in chronic migraine and chronic tension headache. Botox does nothing for the prophylaxis of recurrent episodic migraine in randomized controlled trials.

NEJM  26 Apr 2012  Vol 366
1567   When the first case-series reports of bariatric surgery for type 2 diabetes came out, it was clear that something huge was afoot. In many patients, blood sugar levels dropped and stayed down immediately after surgery, before there was significant loss of weight. Now we have two randomized controlled trials of surgery versus optimal medical therapy in poorly controlled T2DM, and the conclusion of the first paper states that “12 months of medical therapy plus bariatric surgery achieved glycemic control in significantly more patients than medical therapy alone.” I don’t think I’ve ever read such a gross understatement in the conclusion of an abstract—which is such a strange feeling that I don’t know where to put it. “Significantly” here doesn’t mean a statistical trick to magnify an unimportant change in the surrogate end-point of glycaemia. In fact you don’t need statistics at all to describe the success of these treatments: gastric bypass and sleeve-gastrectomy cause massive weight loss (29kg and 25kg respectively) and would have eliminated the need for diabetes treatment in most patients had the HbA1c target not been set artificially low at 6%. The authors commendably advise caution until we have long-term outcomes, and I can hardly object to that. But this is a breakthrough, and will have profound consequences for the future management of T2DM.

1577   The Italian authors of the second paper are equally circumspect in their conclusion, but in the meat of their account of this trial they use the word remission. Biliopancreatic diversion achieved a remission rate of 95% at two years; gastric bypass achieved 75% in severely obese diabetic patients. Whoopee! But that isn’t all. “Preoperative BMI and [postoperative] weight loss did not predict the improvement in hyperglycemia after these procedures.” So these kinds of major surgery have some direct effect on beta-cell function which we don’t fully understand. “Type 2 diabetes”—a complex metabolic disorder, now perhaps curable—has plenty of surprises left up its sleeve. All eyes should be on the detail of what happens following biliopancreatic diversion, in the hope that a simpler form of surgery or some new kind of medical therapy could result. But patience will also be needed: as in all diabetes trials, the outcomes that really matter are cardiovascular events, limb loss, blindness, and renal failure. We still need to be certain we are doing more good than harm.

1596   Diagnosing appendicitis for me is a matter of simple rule-in and rule-out tests in the consulting room. The ones that haven’t made it into the textbooks are the Mars bar test (“if I gave you a Mars bar now, would you eat it?”), the speed bump test (“did you go over any speed bumps on the way here and did you hold your tummy?”), and the hopping test. If any of these are positive, there is a-priori evidence of an inflamed viscus, and the surgeons can work out the rest, especially if there are fever, RIF tenderness, rebound etc. Somebody needs to ascertain the diagnostic characteristics of these “frugal heuristics” which haven’t yet made it into JAMA’s Rational Clinical Examination series. Everything needs to be done to avoid recourse to abdominal CT scanning, which uses frightening amounts of radiation and really should be avoided in children. This study compared low-dose CT with standard- dose CT in 891 patients with suspected appendicitis in a single institution. “Low-dose” is a relative term, meaning about a quarter of standard dose: still very big. The negative surgery rate was the same in both groups, at just over 3%; and the perforation rate was the same too, at around 25%. To me, that suggests too much diagnostic delay: “if in doubt, whip it out,” would be my watchword if I were a surgeon. Perhaps just as well that I’m not.

Lancet  28 Apr 2012  Vol 379
1561   “Unprecedented momentum is gathering to put physics into the centre of global health policies,” declares The Lancet this week. Oops, sorry, that was last week. Let’s try again. “Unprecedented momentum is gathering to put adolescents into the centre of global health policies.” But no, this can’t be the way forward at all. Let’s put some grown-ups into the centre of global health policies. Otherwise we might have editors of international medical journals rushing about like teenagers from one conference to another, blogging crazily and spending all their time on Twitter while neglecting their homework. And that would be terrible.

1591   Peter Rothwell continues his investigation of the long-term randomized trials of aspirin for clues about the possible value of this drug in the prevention and treatment of cancer. Here he generates the hypothesis that the observed short-term reduction in cancer seen in five British trials of aspirin (for cardiovascular protection) may be due to a suppressant action on the mechanism of metastasis, especially for adenocarcinomas, and especially in smokers. This is interesting, but speculative, and these subgroup effects will need to be confirmed by large and lengthy prospective trials.

1602   And then there is the more general question of whether aspirin has the ability to alter what is likely to appear on your death certificate, including the date. Frankly, this is a matter of indifference to me; I take daily low-dose aspirin, but only in the hope of avoiding migraine with aura.

Overwhelmingly, you die of something you can’t avoid, at a time not of your choosing, so it is a waste of time giving the matter any thought. Doctors in the last few decades, however, have taken it upon themselves to try and raise the average age of death in the population by any means possible, in the hope of seeming useful. In a widely discussed earlier study, the Rothwell team showed that daily low-dose aspirin has no effect on cardiovascular mortality in the general population but a detectable effect on cancer mortality. Here they concentrate on the short term reductions in cancer incidence, but get no further in proving any statistically significant overall prolongation of life from the general use of aspirin. The editorial puts this all into context, and also notes the omission of the two largest aspirin trials and other methodological flaws. So take aspirin if you have some reason to, but don’t count on it altering your death certificate.

1613   Kawasaki disease is every doctor’s and parent’s nightmare: cause unknown, so rare that most doctors never see a case, thus easily missed, and potentially fatal due to coronary arteritis. There are about 40 cases a year in the UK, but this Japanese trial managed to collect 298 children with severe Kawasaki’s and randomize them to receive intravenous immunoglobulin with or without prednisolone. The steroid-treated group were left with fewer coronary artery abnormalities.

BMJ  28 Apr 2012  Vol 344
Did you know that a lot of medicine can be done over the telephone? And that if you do that, you can save the NHS more than £1billion per year? No, I didn’t either, but the Health Secretary has evidence that he cannot reveal. As for the evidence we can access, here are two studies in which telephone support was added to routine asthma management, and to smoking cessation aided by nicotine replacement. It didn’t have the slightest effect. So perhaps we need to try harder and target the sickest patients with severe chronic disease. In an astonishing trial on the Archives website, which I shall come back to another time, this is just what they did. Mortality was nearly four times higher in the telemedicine intervention group. A great way to reduce healthcare costs, undoubtedly: do it to enough elderly patients, and you can probably save £3bn.

A useful observational study looks at risk factors for mortality from imported falciparum malaria in the UK over the past 20 years. I can hardly do better than quote the summary, in the hope that colleagues still in UK general practice will take note and keep their radar on: “Most travellers acquiring malaria are of African heritage visiting friends and relatives. In contrast the risks of dying from malaria once acquired are highest in the elderly, tourists, and those presenting in [should be from?] areas in which malaria is seldom seen.” So if they come back from their exotic holiday with “flu,” send them for a blood smear right away.

Arch Intern Med  23 Apr 2012  Vol 172
611   Most of my generalist readers are probably ready to pelt me with rotten eggs when I bring them another paper about stents, but I can’t help telling you about this individual patient data meta-analysis of drug-eluting vs bare-metal stents for primary angioplasty because it’s probably quite important. No, hold the ripe tomatoes too. All I’ll do is give you the conclusion:

“Among patients with STEMI undergoing primary percutaneous coronary intervention, sirolimus-eluting and paclitaxel-eluting stents compared with BMS are associated with a significant reduction in target-vessel revascularization at long-term follow-up. Although there were no differences in cumulative mortality, reinfarction, or stent thrombosis, the incidence of very late reinfarction and stent thrombosis was increased with these DES.”

Yes, read that again. To me that seems to say that these vastly more expensive stents, which also need a year of costly clopidogrel treatment afterwards, don’t actually perform any better than bare metal stents for most patient-important outcomes, and any possible advantages seem to be balanced by disadvantages. Or have I missed something?

623    Another meta-analysis, this time of trials of warfarin to prevent stroke in people with nonvalvular atrial fibrillation. What’s the biggest breakthrough here? Why, it’s making sure people are in the INR target range. Because if they are, they have fewer strokes and fewer bleeds. Medicine is sometimes, though sadly not often, perfectly logical.

Plant of the Week: Cornus florida

I’ve never had much luck trying to grow flowering dogwoods on limy clay and in a Limey climate, but over here in New England they are among the greatest sights of the spring. They are native trees, growing on forest margins, but I haven’t been able to get out and see them in their natural habitat. However, there is little need, as they have been planted by the hundred along the grander suburban streets of New Haven, where the older ones form magnificent mountains of flower in front of huge clapboard houses of various and exotic design.

Except that one should not say “flower” but “bracts.” The true sexual organs of the cornel family are paltry affairs, but they are surrounded by these stupendous quadriform codpieces and crinolines of white, pink or red, presumably to attract the emerging insects of spring. The reddest ones are the creation of human hybridists working with natural sports, and we must be grateful for their patient efforts towards securing a true deep red, most nearly perhaps in “Cherokee Chief.” There is also a purple-leaved form with purple-red bracts, called “Purple Glory,” which I haven’t seen.

I don’t know if there are places in the UK where these trees flourish and display their splendour to an East American degree, but I rather doubt it. For us, they will always bring back memories of wandering down quiet streets of exuberant New England mansions and their gardens in spring sunshine: one of the world’s truly delightful experiences.

JAMA  18 Apr 2012  Vol 307
1583   George Orwell predicted a nightmare world where soothing words would mean their opposites, and gave his dystopia the date of 1984. It was about that year that the term patient centred first appeared in the medical literature, coinciding with the time when the medical-industrial complex went totally out of control in the USA and patients were thrown entirely to the mercy of the market. Books and papers about patient-centeredness (sic) proliferated in America during the 1990s, but the momentum of medicine there has continued to career in the opposite direction. Now that total chaos and unaffordability loom, the US government has set up the Patient Centered Outcomes Research Institute with a hefty budget to find out how to put things right by finding out what systems of care work best for patients. A laudable aim and a fine-sounding name, certain to arouse suspicion among cynics everywhere; but this particular cynic is amazed and optimistic. To find out why, listen to the visionary speech which Harlan Krumholz gave to the PCORI Patient and Stakeholder group a few weeks ago. This goes way beyond the usual rhetoric of being nice and involving patients, and commits PCORI to a radical agenda of patient empowerment – the only way that health systems the world over can reclaim the true purpose of medicine. This article shows how Harlan’s vision is shared by others in the developing organization.

1585   But the moment that you attempt to empower patients, you run into problems. Patients as well as doctors like to believe that there must be a single right answer for every problem, when very often there is not. As I’ve said before, Harlan’s surname (meaning crooked wood in German) always reminds me of Kant’s famous dictum, “out of the crooked timber of humanity, no straight thing was ever made”. And it’s no good torturing the evidence by exercises in subgroup analysis and modelling: in most of medicine, there is irreducible uncertainty. Here is a nice short philosophical piece by David Kent and Nilay Shah, headed with the splendid observation of George Box that All models are wrong, but some are useful.

1587   Three non-clinicians discuss the problems of continuous patient engagement in comparative effectiveness research. Now comparative effectiveness research is actually fiendishly difficult, for reasons I will try to outline very briefly in a moment; and securing patient involvement in research is also difficult, but absolutely essential. In fact it will be a measure of PCORI’s success if it can demonstrate that every aspect of its research is genuinely patient-centred – i.e. that it listens to the patient voice at every stage, and that every output has direct bearing on decision making with patients and society. The ultimate measure of its success, ironically, will be the disappearance of the concept of the patient altogether.

1593   In this hefty themed issue of JAMA, there now follow five examples of comparative effectiveness research (CER), followed by a knotty editorial with the title Is It Time for Medicine-Based Evidence? And here is the problem for you and for me, dear Reader: you cannot properly assess a paper on outcomes research or CER without some understanding of the following methods – multiple linear regression or analysis of covariance for continuous (dimensional) outcomes, logistic regression for binary (dichotomous) variable outcomes, proportional hazards analysis or Cox regression when a time interval is relevant to a binary outcome (i.e. survival analysis), and Poisson regression when outcomes are measured as counts. Moving on, you then need to employ these techniques in one or both of two conceptual processes which can help to balance the characteristics of unmatched groups in observational studies: propensity scores and instrumental variables. There are plenty of statistics texts to confuse the unwary, but there is no simple, comprehensible guide to outcomes research for the non-specialist. I know, because I am trying to help write one. And I am hoping somebody else will deal with all this while I write about patient-centredness. So finally, back to this study. You need not read it: it is simply a good teaching example for those who want to understand the use of propensity scoring in retrospective cohort studies. The study concludes that without needing a randomized controlled trial, we can be pretty certain that adding bevacizumab to carboplatin-paclitaxel chemo for advanced non–small cell lung cancer makes no difference. And that is useful knowledge for decision-making.

1602    So we’re getting accustomed here to the idea of extracting useful knowledge from unbalanced observational data. To do this requires both sides of the brain. Your left brain can immediately busy itself with the data, using extension tools like statistics software packages and tabulation methods. Here we’re looking at nearly a quarter of a million American adults with serious trauma transported to hospital either by ground or by helicopter. What does your right brain tell you about this problem? Mine tells me that you cannot match these groups because there are simply too many confounders. But the left brain goes ahead and tries, using every gizmo it can lay its hand on. After performing all its tricks, it reports that there is an absolute mortality benefit of 1.6% in those transported by helicopter, and a small benefit in functional outcomes. And what does my right brain say about that? That you still cannot be certain you have really corrected for confounders to that level of difference, and that even if you had, it would be no argument to buy more helicopters as a strategy for improving trauma outcomes.

1629   Let’s skip to the final study of the 5, which uses an instrumental variable approach to account for measured and unmeasured differences between patients with clinical stage T1a kidney cancer treated with partial or radical nephrectomy.

Briefly, the instrumental variable approach identifies an instrument (variable) that is thought to be associated with the treatments of interest but not with the outcome. Here there is a very striking difference in long-term outcomes: the hazard ratio for death in those treated with partial nephrectomy rather than radical is 0.54. Although my left brain struggles to follow every stage of the methodology, my right brain tells me that a difference of this magnitude is unlikely to be due to skewed assumptions or residual confounding.

NEJM  19 Apr 2012  Vol 366
1467    Now that we’ve finally escaped from JAMA and all this stuff about CER methodology, let’s look at this first paper in the New England Journal. Being in the NEJM, funded by the NHLBI and conducted by a distinguished team of researchers, it must be right, and it concludes that “In this observational study, we found that, among older patients with multivessel coronary disease that did not require emergency treatment, there was a long-term survival advantage among patients who underwent CABG as compared with patients who underwent PCI.” Proof at last of what we all suspected: new tubes must be better than stents. But hang on, what was the absolute mortality difference between these groups? The median follow-up period was 2.67 years, at which time the survival lines were beginning to diverge in favour of CABG, but not by very much. In the minority of patients followed to 4 years, the difference was statistically significant and stood at an absolute value of 4.4% provided one accepts the methods of the study. And what are these methods? Why, our new friends propensity scores and inverse-probability-weighting adjustment. So we are back to the problems of comparative effectiveness research with a vengeance. The left brain, without the help of complex statistical computation, cannot interrogate these results; while my creaky old right brain tells me that I cannot make use of this information in decision-making with patients, because there are too many variables to rely on such small differences. In fact I think we may need new methods of describing the confidence limits when using these two-stage weighting adjustments with unbalanced groups. So do we need another RCT comparing CABG with PCI using current methods? The editorial discusses this question, but not with any satisfactory conclusion. I think equipoise still best describes the clinical situation.

1477   Yippee! We’ve finally got away from CER and on to the best kind of medical paper – a randomized controlled trial conducted without industry funding, with a clear result that will be of benefit to thousands of patients with muscle-invasive bladder cancer. And British too! The simple trick is to give chemotherapy using fluorouracil and mitomycin C at the time of radiotherapy. This provides a sustained survival advantage without a significant increase in adverse effects.

1489   And now, like a Common White Butterfly, we must return to the field of cabbage. CABG can, as all of you know, be performed with a cardiopulmonary bypass pump or without. Off-pump CABG is technically more challenging but is supposed to reduce the amount of debris reaching the brain during surgery. This trial (given the unoriginal acronym CORONARY – how much jollier BRASSICA might have been) randomized 4752 patients in 79 centres to have their cabbage done one way or the other. At 30 days, there was no significant difference in gross outcomes, but they acknowledge that “Neurocognitive outcomes and economic data may have an important effect on and substantially influence the ultimate interpretation of the primary findings.”

1515   Here’s a good update on alopecia areata, a T-cell–mediated autoimmune disease in which the gradual loss of protection provided by immune privilege of the normal hair follicle plays an important role. But I must leave you with these bald facts and rush forward to the remaining journals.

Lancet  21 Apr 2012  Vol 379
In his Offline column this week, Richard Horton tells us that this physics-themed issue of The Lancet is timed “to coincide with the death of Albert Einstein on April 18, 1955.” Now this is an idea that Einstein would appreciate: what, after all, are 57 years and 3 days in the continuous fabric of space-time? In fact Einstein once wrote a letter of consolation to a bereaved friend using this idea. Or, as TS Eliot more gloomily declares as the beginning of Burnt Norton,

Time present and time past
Are both perhaps present in time future,
And time future contained in time past.
If all time is eternally present
All time is unredeemable.

RH reaches similar heights of mysticism as he tells us why physics is special. He had discovered that underlying everything in the material world there is physics. It follows, he declares, that “Physics is at the heart of our society and so our understanding of health.”… “all of us interested in the future of healthcare, should declare and implement a passion for physics. Our Series is our commitment to do so.” Yes indeed. Perhaps it is also time for our column to be renamed Offwall.

1489   My old practice used to number amongst its diabetic patients a Canadian lady who had been treated by Banting in the 1920s: she owed a 60 year extension of her life to the insulin he had just isolated from the pancreatic cells of animals. Animal insulins were still the only kind in use when I first took up doctoring, and very good they were. Many patients complained of hypoglycaemia without warning, and erratic control, when they were replaced by human insulins in the 1980s. But despite their lack of demonstrable superiority, these had almost entirely replaced the cheaper, older insulins within a few years. Insulin manufacturers managed to develop a highly effective mechanism for disseminating their expensive new products by means of trials sponsored by industry, peer pressure from academic diabetes centres receiving large funds from industry, and primary care nurses trained by industry. This mechanism was put into action again in another huge wave of marketing once the patents on human insulin expired, and the so-called analogue insulins – modified by a peptide of two – took over, further ratcheting up costs without any improvement in outcomes. The effect has been to make insulin treatment unaffordable in some developing countries. But still the search for profits goes on. The latest trick is to produce ultra-long acting insulins such as NovoNordisk’s insulin degludec and seek to prove their advantage over existing basal insulin regimes. This trial in type 1 diabetes shows overall equivalence with insulin glargine, including in the incidence of hypoglycaemia. But fewer of these episodes occurred at night with degludec. In a trial in type 2 diabetes, the rates of hypos with degludec just managed to squeeze under the statistical bar and come out lower than glargine (95% CI 0.58-0.99). On open-label, manufacturer-sponsored trials of this sort do billions of dollars’ worth of sales depend. The Lancet chooses to devote most of its research space this week to them, perhaps expecting good sales of reprints. It would be good to be told.

1551   Having declared his passion and commitment to physics, complete with the Royal We, Richard Horton has managed to pull in a singularly weak set of contributions for his Physics and Medicine series, the strongest of which is the last – mainly because it is much more about biology than about physics. It’s a fascinating exploration of such things as fractal patterns in nature and the problems of scale in biological systems, and I would strongly recommend it.

BMJ  21 Apr 2012  Vol 344
As always, there are plenty of good things to read in this week’s BMJ. I would particularly recommend Iona Heath’s beautiful lament on the demise of the NHS -how a war-ravaged generation strove to create a fairer society, and how we are strangely set on destroying it; and Margaret McCartney’s piece on why screening for streptococcus B in pregnancy may not be the unmixed good it is portrayed as in British newspapers. As for original research, there is PhD student-led systematic review of metformin plus insulin versus insulin alone in type 2 diabetes. “There was no evidence or even a trend towards improved all cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes. Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control.” I used to think that the last 40 years of diabetes research had yielded just one fact that one could rely on: metformin is a good drug. Now, sadly, I’m not even sure about that.
Physicist of the Week: Michael Faraday

I – or rather We – declare and implement our passion and commitment to physics by this unique celebration of the life and work of Michael Faraday, timed to coincide with his death on 25th August 1867, give or take 145 years and a few months.

Faraday is the physicist everyone can love because he was kind to children and animals, and bad at maths. He led a life of blameless application, humility, piety, kindness, and good sense: in fact his life, shorn of the physical discoveries, is literally too boring to read about. If you want proof, try Michael Faraday (1864), by John Hall Gladstone, free on Kindle. You will do better with The Electric Life of Michael Faraday (2009) by Alan Hirshfeld, a physics professor who explains some elements of Faraday’s conceptual achievements, but fails utterly to match the drive and luminosity of Richard Holmes describing Faraday’s mentor Sir Humphry Davy in The Age of Wonder. Faraday needs a biographer to match his stature. A really able writer with a knowledge of science is needed to explore the paradox of a man who achieved amazing feats through a mixture of conceptual freedom and endless meticulous experiment. Although Faraday was a religious fundamentalist, his God was the very opposite of Newton’s (or Milton’s) determinist tyrant, playing with billiard balls of all sizes from the atomic to the cosmic. Faraday dismissed ball-atoms and action at a distance: for him forces existed as fields and vibrations, and without a single mathematical equation he worked out the basis of electromagnetism and went a long way towards relativity and the modern view of the atom.

Einstein always kept a portrait of him in his room. It took the genius of Thomson and Clerk Maxwell to create what we now recognize as the mathematical physics of the later nineteenth century out of the qualitative experimental descriptions of Faraday. While they toiled on the equations, he slipped gently into senility – childless, blameless, and finally wordless: a strange and rather haunting hero of science.

JAMA  11 April 2012  Vol 307
1489   The new editor of JAMA feels that his worthy journal needs a bit of livening up, and who can disagree? He has borrowed an old idea from the BMJ, in the form of head-on for and against articles. “Should a 55-year-old man who is otherwise well, with systolic blood pressure of 110 mm Hg, total cholesterol of 250 mg/dL, and no family history of premature CHD be treated with a statin?” This is an awful question for several reasons. It implies that the doctor is the one who should decide, and the “patient” is the object who should, or should not, “be treated”. But in what way is this man a patient?  Why is he “otherwise” well? Is his illness being 55, having low blood pressure, or having a total cholesterol of 250 mg/dL? In this exchange of views, three doctors think he should “be treated”, and two doctors (one the editor of Arch Intern Med) think he shouldn’t. I would argue that it is none of their business: give him the evidence and let him decide.

1497   Gah, this is so boring! Are major and minor ECG abnormalities associated with coronary heart disease events? Yes. Does this mean that everybody should have a regular ECG? No. And why? Oh for goodness sake don’t bother me—just go back to medical school or read Overdiagnosed.

1506   Next a Danish nationwide database study looking at everyone over 45 admitted with heart failure for the first time and treated with an angiotensin receptor blocker. Does it make any mortality difference whether they are given candesartan or losartan? No, provided they are given a decent dose (100mg losartan).

1513   If you aren’t in America, why should you read a paper on eliminating waste in US healthcare? Two reasons—first it’s by Don Berwick, and anything he writes is worth reading (though if you only have time for one piece, make it The Epitaph of Profession); second it has lessons for all health systems. Especially the NHS, as it becomes a feeding trough for all those nice private providers that MPs and Lords have shareholdings in. Failure to deliver the most effective care, failure to coordinate care properly: on these counts the NHS does very well compared with the US, but will improvement continue? Overtreatment, administrative complexity, and fraud and abuse: what can we look forward to on these fronts? Surely the noble guardians of our legislature will protect our healthcare system from any such taint.

1517  The Rational Clinical Examination series may be struggling to maintain the standards of its glory days, chiefly because it is running out of topics: but blunt intra-abdominal trauma is a great topic and gets a great discussion. When I last worked in an emergency room, handheld ultrasound hadn’t even been invented, but it now comes out top in investigative usefulness, though it can’t entirely rule out a damaged viscus. If you deal with this kind of scary emergency, this paper is a must-read: and you also ought to be thinking about designing some on-the-ground research, since more is clearly needed.

NEJM  12 Apr 2012  Vol 366
1382   Another week, another drug which prolongs progression-free survival by about 4 months in an incurable cancer. This week it is the turn of olaparib, an orally available PARP inhibitor, for maintenance therapy in platinum-sensitive relapsed ovarian cancer. But the tale does not end with AstraZeneca taking this drug to the FDA for approval for ovarian cancer, and marketing it at the usual price of about $10k per month gained. Instead the company has recognized that there was no overall mortality benefit and has dropped the drug for this indication. Is this a welcome sign that “progression-free survival” is losing credibility as a meaningful end-point in cancer trials?

1393   Coronary computed tomographic angiography (CCTA) is a high-radiation procedure which is very good at ruling out significant coronary artery disease. This important study from the Commonwealth of Pennsylvania shows that it can be used in emergency departments to rule out coronary ischaemia at the cause of chest pain in patients with low-moderate probability. That way more patients can go home more quickly. But I can see drawbacks. For a start, CCTA picks up coronary artery disease in 9% of these patients, as opposed to a 3.5% pick-up rate if CCTA is not used. A lot of this will represent overdiagnosis of asymptomatic disease, and may lead to further (radiation- and cost-intensive) investigation. Secondly, the routine use of CCTA to save an average of 6 hours waiting for biochemical tests will drive up costs and increase the “defensive” use of radiation, meaning that in some instances patients going to different hospitals with recurrent non-cardiac chest pain and getting pretty massive cumulative X ray doses. I think this is a development to be welcomed with caution.

1404   Vorapaxar is a novel antithrombotic agent which works by preventing thrombin binding to platelets, by blocking the protein-activated receptor (PAR-1). To test such agents these days requires enormous trial sizes—this one recruited 26,449 subjects with a history of myocardial infarction, ischaemic stroke, or peripheral artery disease to see how well it prevented further events. The prize for Merck would have been a new blockbuster drug for the whole secondary prevention market. But fate, bleeding fate, intervened and the trial was halted. There were fewer ischaemic events in the group who got vorapaxar rather than a thienopyridine, but more cerebral haemorrhage. Vorapaxar is an interesting drug which may have some kind of future, but blockbuster it is unlikely ever to be.

Lancet  14 April 2012  Vol 379
1393    In 1998, when I first started writing these brief notes on the journals for a few friends and colleagues, I decided that coronary artery stents were an interesting new development that I should tell people about whenever they cropped up in the literature. How dearly I (and you who have followed me) have paid for that decision! Paclitaxel, sirolimus, everolimus, zotarolimus… I have tried to make them interesting by pretending they were creatures from Star Wars, or minor characters from Antony and Cleopatra, or members of a zany family called Olimus, whose next son will no doubt be called boralotimus. And now it turns out we may have been looking at the wrong thing all along: what matters in the Stent Wars is not the drug these things elute, but the metal they are made of. According to this “comprehensive network meta-analysis” of 49 trials with 50,844 randomly assigned patients, the clear winner is a cobalt-chromium stent which elutes everolimus. For the first time in 14 years, my remarks on stents will actually be read by some interventional cardiologists, thanks to their appearance on the CardioExchange website run by the NEJM. OK you guys, start quarrelling about this study: the rest of us are off for a nice snooze.

1403    Now children, what happens if you give somebody with type 2 diabetes a drug which increases endogenous insulin secretion? Their sugar levels go down, yes. If the drug is a sulfonylurea like glimepiride, they also have a risk of hypoglycaemia, and they may lose beta-cell function more rapidly. And don’t forget that UKPDS tells us that if you combine a sulfonylurea with metformin, you end up with increased mortality—but that is by the way. In the phase 2 trial reported here, the investigators aren’t interested in crude measures like coffin counts. Takeda have produced a new diabetes drug which works by activation of the free fatty acid receptor 1 (FFAR1), and it seems to stimulate insulin production and reduce blood sugar without any serious risk of hypoglycaemia. That’s about it for now. The drug TAK-875 doesn’t yet have a name and needs some phase 3 trials. Let’s hope that these are double-blinded trials of this single drug, of sufficient power and duration to determine real microvascular and macrovascular end-points. Let’s hope that the licensing authorities insist on such evidence, even though it may take five or more years to gather, and disregard all surrogates such as HbA1c, creatinine/albumin ratio, lipid fractions, rate of retinal changes, doubling of creatinine, etc etc. That way, for the first time in the history of type 2 diabetes, we might actually know what a specific treatment does to patients.

1412    Adolescence is a state from which most of us eventually recover. In some youths it is characterised by periods of chronic fatigue, and if these persist for a long time, they become chronic fatigue syndrome. I suspect that many factors often conspire to perpetuate CFS in adolescence, which can have devastating results for social development and education. The sensible Dutch have now devised a web-based cognitive intervention called FITNET, and in this trial it achieved spectacular success at six months: 75% school attendance and 85% absence of severe fatigue, compared with 16% and 27% respectively with usual care.

BMJ  14 April 2012  Vol 344
Health literacy is the subject of this survey of English adults. It’s a term which has spread widely in recent years. In the grim judgemental days of my youth in Yorkshire, where everything carried its due apportionment of blame, people were graded according to intelligence, and separately graded by education, and further graded by literacy; but never graded by “health literacy” because health was not the kind of thing that proper Yorkshiremen were permitted to worry about. I think this composite term is useful for allowing us to address the fact that a third of the population lacks the ability to understand basic written health information. That does not mean that they are beyond the reach of explanation, or cannot share in the making of decisions about their care: it just means that it needs to be done in different ways, both directly and with the use of video. And low health literacy is of course associated with lower levels of health and poorer health outcomes.

Migraine with visual and sensory aura is a peculiar phenomenon, which I have had a lot of chances to observe lately, but cluster headache belongs to a different league of pain and autonomic dysfunction. Before the arrival of triptans and the discovery of high-dose oxygen as a treatment, I remember having to pretty well flatten patients with opioids to combat the intense pain and distress. Billed as the first review of the condition in the BMJ for fifty years, this one could hardly be bettered, and ends with a brief narrative from a patient who sought to beat her head with a telephone handpiece to relieve the pain, while trying to stop her children from noticing.

Arch Int Med  9 Apr 2012  Vol 172
555   Scraping the barrel of things to watch on Netflix the other night, we ended up sitting through a suitably interminable account of the 4,300 mile journey of exploration by Lewis and Clark in 1804-6, of the Louisiana Territories purchased by Thomas Jefferson. As they moved upstream, the diet of their men changed from ordinary beef to bison, then horse, then elk, and antelope: when they reached the Western side of the Rockies, the river beneath them was thick with huge salmon, but such was their yearning for red meat that they preferred to barter with the local tribes for fattened dogs. Oh dearie me, how very unhealthy! Amazingly, none of them died on these epic travels through often hostile territory, and one or two made it beyond the age of 90. But we should not draw the wrong conclusions from this, because red meat consumption is once again shown in this study to be associated with an increase in total mortality and mortality from cardiovascular disease and cancer. There are many reasons why one should perhaps consider giving up red meat; personally I would not rank longevity as high as the feeling inspired by our next Netflix offering, Buster Keaton’s Go West (1925), in which he is movingly befriended by a young cow called Brown Eyes.

Plant of the Week: Linnaea borealis

It is a nice touch that Carl Linnaeus, who was extravagantly vain in so many ways, chose this humble mountain alpine plant as the bearer of his name. It is a small ground-hugging relative of the honeysuckles, with lovely little elongated bell-flowers of white streaked with purple, said to be fragrant if you care to bend to within a few inches of the ground.

We went searching for spring wild flowers in the mountains of upstate Connecticut, and the Linnaea was all we found: the trilliums were not yet out. It a lovely little thing which I assume does well in colder gardens on acid soil. The plant we found used to be called Linnaea americana, but botanists have changed their mind and declared that just as there was only one Linnaeus, so there shall be only one Linnaea.

Sumerian Proverbs for Medical Editors

There will be a prominent place for a capable scribe

A good word is a friend to numerous men

Good fortune [calls for] organisation and wisdom

Accept your lot and make your mother happy

Ignoramuses are numerous in the palace

From many oxen, is there no dung?

clay tablets from c 2000 BC

JAMA  4 Apr 2012  Vol 307
1394    A special dread settles on me this week as I know I am going to have to write about breast cancer screening. But let’s leave the dread question of whole-population mammography for later, and consider the add-on benefit of annual ultrasound or single-screening MRI in selected high-risk women. While the war over breast screening rages unchecked in the letters and a book review in this week’s Lancet, let’s take refuge in this little corner of the battlefield, where at least the fog of war is not too thick and we can count a few weapons and estimate a few casualties. The volunteer combatants are women with dense breasts and at least one factor that increases their risk of breast cancer. The ultimate proof of victory, as in all screening studies, will be a reduction in total mortality. The casualty list should include every woman undergoing biopsy or surgery, because nobody comes away from these things altogether unscathed, be it mentally or physically. This study gives us a casualty list, including the number of enemy killed (breast cancers detected and operated on), but cannot give us any idea of the extent or the cost of victory, because it was run over a three-year period only. Our brave lasses certainly saw their share of action: 2725 over the age of 25 (!) went through annual mammography and ultrasound, and 612 ended up having MRI. During that time 110 had 111 breast cancer events: 33 detected by mammography only, 32 by ultrasound only, 26 by both, and 9 by MRI after mammography plus ultrasound; 11 were not detected by any imaging screen. Enough. We can tell from these figures that the three imaging modalities will pick up most cancers; but the true cost—mentally, physically, and financially—can only be hinted at in a study like this. Only very long-term follow-up will give us a true estimate of overdiagnosis and the degree to which such screening detects cancers which would never progress. But in just these three years, a total of 1272 biopsies were performed—more than ten for each cancer detected. So this high risk group may well see a small reduction in all-cause mortality over the course of their “screening lives,” but it will be purchased at a high cost in medical procedures and anxiety. In fact any woman undergoing this cycle of procedures would be extremely lucky to get away with a single fine-needle biopsy during her life—two or three would be more likely.

1414  Oral fluoroquinolones are cheap and ubiquitous these days, and lots of doctors take them abroad in case of traveller’s diarrhoea. But beware: this case-control study confirms that they may carry a more than fourfold risk of retinal detachment. OK, still not a huge absolute risk, and usually fixable; but it may not be what you want to happen to you while you are cruising down the Nile, admiring Cambodian temple complexes, or trekking to Machu Picchu.

NEJM  5 Apr 2012  Vol 366
1287   The successful EINSTEIN-PE trial of rivoroxaban has been talked about for a while, and you don’t have to be Einstein to work out that this is very good news for Bayer HealthCare and Janssen Pharmaceuticals, who co-funded the trial. It was an open-label trial, pitting the new oral fixed-dose factor Xa inhibitor against an adjusted-dose vitamin K antagonist (in the States, they use dicoumarol as well as warfarin) for 3, 6, or 12 months after symptomatic pulmonary embolism. As far as I can tell (and you know I am far from infallible) the stuff did what the manufacturers put on the can: rivaroxaban was as good at preventing recurrences, and less likely to cause major bleeds than a coumarol/INR regime.

1298   This trial comparing two artesunate-based antimalarial regimens in patients with uncomplicated falciparum malaria is principally a fairly routine affair of showing that pyronaridine–artesunate was noninferior to mefloquine plus artesunate for the primary outcome. This is useful knowledge for those in the field, across Asia and Africa. But the study has rapidly become more famous for the unwelcome confirmation it brings of artemesinin resistant malaria in Cambodia. This is suggested by increased parasite clearance times in a subset of patients from the region which first produced strains resistant to previous antimalarial drugs. Those lethal little zoites may be on the verge of outwitting us yet again in the jungles of IndoChina: a sickening thought, after so many decades of effort, never quite sufficiently carried through.

1310   Here’s a really thought-provoking study from Sweden showing that in the week after receiving a cancer diagnosis, the relative risk of suicide goes up by 12.6 and the RR for cardiovascular death by 5.6. Taken over the first year, the risk ratios are slightly over 3 for both. The immediate cardiovascular effects of a shocking diagnosis could hardly be more dramatically demonstrated, while the continuing physical effect could be partly explained by prothrombotic and inflammatory effects from the cancer itself. But the suicide figures once again raise the question of what is an “appropriate” response to a cancer diagnosis. Palliative care specialists, at least in the UK, share a religious predisposition to expect all cancer patients, at whatever stage, to bear their sufferings to the end, encouraged by promises (which may be undeliverable) of complete relief. To me personally, this interpretation of the will of God seems neither rational or generous, nor even always honest. The original Zarathustrian religion of good thoughts, good words, and good deeds seems to me a better guide: it acknowledges that God (or good, or whatever you want to call it) can only act through man in the physical world. Suicide in the first week of diagnosis is likely to be an immediate distress reaction, almost certain to cause a lot of distress in others: it is not irrational, but is usually best averted if possible. But well-planned suicide in the face of impending suffering and death does not seem to me either irrational or ignoble, provided it is done with full consideration to others.

1319   The ancient Good Religion of Zarathustra dominated Iran for at least a thousand years, before the Arab conquest gradually led to the imposition of Islam from the mid-seventh century onwards. The Muslim tradition in Persia contains elements of both, as shown by the linguistic parentage of the name Faramarz Ismail-Beigi. How nice it would be to dwell on the history of this wonderful part of the world a little longer, but unfortunately we must move on to the topic of glycaemic management of type 2 diabetes mellitus, upon which the distinguished Dr Ismail-Beigi writes in this week’s NEJM. You may perhaps be expecting some harsh words from me on this subject, but I must honour the Iranian tradition of intelligence, charm, and moderation as best I can on this occasion. Professor I-B acknowledges that there is a lot we do not understand about the disordered metabolic state that we please to call “type 2 diabetes,” on the grounds that it is characterised by high levels of blood glucose and gradual depletion of beta-cell function. He goes through the evidence and finds that it is insufficient to guide any choice of agents beyond diet and metformin in the first instance. Pretty well everything we know about long-term effects—whether driven by treatment or disease processes – is derived from a single study designed in the 1970s, the UKPDS. Survivors of this group who were treated intensively at the outset with sulfonylureas and insulin show a “legacy effect” according to levels of blood sugar control, which the investigators attribute to the treatment—though not to the extent of suggesting we use these interventions as first-line treatment in 2012. Rather we should look at the subgroup of fatter patients who were given metformin, and extrapolate from them, since they had somewhat better outcomes. We should hope that these newly diagnosed patients maintain a glycated haemoglobin level of around 6-6.5%, as people who managed to stay at these levels did best in the long term. We can’t tell whether this was due to treatment or because they had a more favourable disease process. This may not be the pinnacle of evidence-based medicine, but it is what specialists agree on when they meet in High Council to discuss what we should do with tens of millions of people with this condition around the world, basing their judgements on what happened to a few hundred British diabetics from the time of Mrs Thatcher. For more modern sugar-lowering interventions, we have no long-term data on harms or benefits, since no-one has thought it necessary to require them. About all this, Faramarz Ismail-Beigi is quite candid, calm, and polite: so in the best tradition of Persian courtesy, I shall stay the same towards the whole profession of diabetology. Salaam, Khoda hafez.

Lancet  7 Apr 2012  Vol 379
1310   This cluster-randomised trial from British general practice compared computer-generated reminders about medication dangers with something they grippingly called PINCER—“a pharmacist-led information technology intervention, composed of feedback, educational outreach, and dedicated support.” You can choose which you hate most—this description or the acronym. The end-points were: non-selective non-steroidal anti-inflammatory drugs (NSAIDs) prescribed to those with a history of peptic ulcer without co-prescription of a proton-pump inhibitor; β blockers prescribed to those with a history of asthma; long-term prescription of angiotensin converting enzyme (ACE) inhibitor or loop diuretics to those 75 years or older without assessment of urea and electrolytes in the preceding 15 months. Fair enough, I suppose (though I suspect some surprises when someone eventually looks at the end-points in “asthma” patients given very low-dose β blockers versus those given β agonists): and of course the PINCERed practices did better. So what should you commissioning guys invest in? More paid-for interference—sorry, I mean outreach and dedicated support—by community pharmacists, or punchier, clearer computer reminders?

1331   “Knee-replacement surgery is frequently done and highly successful.” I can vouch for that—not because I’ve had it, but because a lot of my patients had it done by the first author of this review, and they have fared well. During my GP career, I’ve seen this procedure grow up from a last-resort, almost experimental operation to a routine procedure for painful osteoarthritis. The technology seems to have improved steadily over that time, though with the present pitiful standard of device regulation, there is nothing to stop some new prosthesis winning most of the knee surgery market before it turns out to be a disaster. I refer of course to the metal-on-metal hip scandal; but I’ve seen it happen with some other kinds of innovative knee surgery, like the carbon ligaments once favoured by another local surgeon. The international epidemiology of TKR is fascinating for its insights into the variability of preference-sensitive surgery in different health systems. In the UK, demand for TKR may actually have peaked—or is it just being rationed more effectively?

BMJ  7 Apr 2012  Vol 344
Ah, a plate of plain white rice. How like the research pages of the BMJ this week: bland, unappetizing, and badly in need of some original additions. Maybe that’s why the journal let through this terrible study which traces the links between white rice consumption and diabetes, by a series of population survey methods which have BEWARE OBVIOUS CONFOUNDERS written all over them: perhaps they just wanted newspaper coverage and rapid responses. They certainly got plenty of the latter, and I will let them do their work unhindered by any further comment from me.

Well, maybe this is interesting, if it is confirmed in other studies: women who have had surgical treatment for treatment for human papillomavirus-associated vulval or cervical disease are less likely to experience recurrence if they have had previous vaccination with quadrivalent HPV vaccine. This is based on retrospective pooled data from interventional trials.

Anns Intern Med  3 Apr 2012  Vol 152
491   And now, as I warned you, we must return to the battlefield of breast cancer screening. I defy anyone to reach clarity on this subject: the nature of the data just doesn’t allow it. So we are on the horns of a real dilemma here. We need women to make up their own minds on whether to go for this kind of screening, but we cannot inform their choice in a way which is either easily comprehensible or free from our own value judgements. By saying this, I’ll probably draw fire from both sides in this debate—the screening enthusiasts who will say there is clear evidence of benefit and women shouldn’t worry their pretty little heads about the matter but just go along and have their breasts X-rayed; and the sceptics, led by the redoubtable Peter Gøtzsche, who will say that the benefits are dubious or non-existent and the harms are all too real. Each side will then go through a selection of mainly observational studies to try and prove their point. At this point I tend to find some excuse to slip out of the room, glad that I am a man, and that I no longer have to give my advice to anyone: muffled cries of anger pass me by as I make my escape. But for your sakes, dear readers, let’s take a passing look at this latest observational study from Norway. Leave aside the costs, the anxiety, and the needle biopsies and concentrate on how many detected cancers can be considered as overdiagnosed. “The number of cases of breast cancer found in screened women was compared with that in matched unscreened women. Investigators estimated that 15% to 25% of cases of breast cancer detected represented overdiagnosis.” OK guys, you be downloading the paper and discussing the methods, and the meaning of “overdiagnosis.” I’m just nipping out to get some coffee…

Plant of the Week: Ribes x gordonianum

The flowering currants are classic spring bushes to be looked forward to with special pleasure. As forsythias scream their yellow at the spring winds, hard by battered expanses of browning magnolia flower, and cherry trees filled with blowsy pink, it’s a relief to look down at or below head height and see the intriguing brick and pinkish yellow flowers of this unassuming but essential little shrub.

It is a quintessentially British plant, discovered as a chance hybrid in Ipswich in 1837. It carries the reds of Ribes sanguineum subtly blended with the yellows of Ribes odoratum, in open clusters of small bell-shaped flowers with bright yellow and red stamens. I keep trying to detect the spicy fragrance of odoratum but the feral rankness of currant-bush tends to predominate. Nonetheless, this tousled, prickly, loveable scamp should be in every garden to welcome the spring.

JAMA  28 Mar 2012  Vol 307
1257    Medical conferences exist to affirm everything that hinders the progress of medicine as a compassionate and honest enterprise. They are a showcase for authority figures, pharma-funded research, half-completed work in the form of abstracts and late-breaking sessions; they use up prodigious amounts of money and carbon fuels; they reward high-tech flashiness and set no value on basic care and joined-up thinking: they reinforce a career structure and a social hierarchy in medicine which undermines the whole concept of patient-centredness. I’m glad to see all these feelings shared by John Ioannidis in this Viewpoint piece. John is a famous iconoclast who wrote the classic 2005 PLoS Medicine paper, Why Most Published Research Findings Are False. Here he proposes that nobody with any ties to industry over the preceding 3 years should be allowed to organize a conference. Also, that in order to ascertain the educational benefit of conferences, the next one should be randomized.

1273   Look into your hearts, my brothers and sisters! How few of you are saved from the perdition of cardiovascular risk! Just 1.2% of Americans can count themselves truly upright, by not smoking; being physically active; having normal blood pressure, blood glucose and total cholesterol levels, and weight; and eating a healthy diet. The rest are mired in sin—by genetic predestination or moral turpitude; and the world grows ever less righteous. According to the John Calvin of epidemiology, the late Geoffrey Rose, cardiovascular disease should have doubled since 1992, when he published his book The Strategy of Preventive Medicine. Instead it has halved. How depressing it must be for the Calvinists when so many sinners fail to die.

1307  One reason that so many sinners survive is the widespread use of statins in high-risk patients. Wistful for the enormous profits that these drugs brought in during the last two decades, pharma companies continue to search for a lipid-lowering drug which will add to the effect of HMG co-reductase inhibition. So what is the lipid subfraction that most predicts risk in people taking statins? Here’s a painstaking individual patient data meta-analysis showing that it is not low-density lipoprotein cholesterol alone, nor apolipoprotein B, but the totality of non-high-density lipoprotein cholesterol. Lower this, and you may have the next lipid-lowering blockbuster; or you may have nothing; or you may kill people.

NEJM  29 Mar 2012  Vol 366
1181, 1190   “Few adverse effects were observed, and few patients withdrew from the trials. Nevertheless, a 12-week follow-up period is too short to assess the safety of treatments targeting interleukin-17. Future trials involving larger numbers of patients treated and followed for a much longer period of time will be needed.” So says the sage editorialist, who also explains the interleukin 17 system and many other arcane pathways that may be involved in psoriasis. Nevertheless, the NEJM has thought fit to publish these trials, no doubt because we would all like to see better treatments for psoriasis, and this approach shows promise. It could also be that these papers may help Amgen and Eli Lilly get FDA approval for brodalumab and ixekizumab, respectively. As I’ve said before, the companies may find the need to buy many reprints of these papers from the NEJM: this has happened before, and is part of the normal business structure of medical publishing, hidden behind a wall of commercial secrecy. Whether this results in the best selection of studies, or improvement of clinical practice, is for you to judge.

1209   I have written a lot about patient-important outcomes in type 2 diabetes, but one that we can easily overlook is mobility. In obese people with T2DM, loss of mobility leads to a downward spiral of diminished energy loss, muscle atrophy, and increase in adiposity: worsening glycaemic control then leads to all the problems of insulin therapy in people who cannot exercise and are insulin resistant. We have all seen this happen to our patients, and it is likely to become a commoner sight throughout the world unless we can find an effective intensive lifestyle intervention—one that can be applied to millions of individuals. The Look AHEAD trial enrolled more than 5,000 patients and achieved a 40% reduction in loss of mobility over 4 years in its intensive intervention arm. This could be of generalizable importance. Methodology buffs will also be impressed with the sophistication of the analysis: “We used hidden Markov models to characterize disability states and mixed-effects ordinal logistic regression to estimate the probability of functional decline.” A worthwhile paper.

1227   Blindness is certainly a patient-important outcome in diabetes, and here is an excellent and optimistic review of diabetic retinopathy. Optimistic because the incidence of diabetic retinopathy is falling, and there are effective new treatments based on vascular endothelial growth factor (VEGF) inhibition. It is worth mentioning in passing that despite popular myth, glycaemic control has only a minor effect on eye disease in T2DM. The role of VEGF in the process, however, is crucial. Intravitreal glucocorticoids and VEGF inhibitors are playing an increasing role in the treatment of established eye disease. Intriguingly, inhibitors of the renin-angiotensin system have been found to confer specific protection against retinopathy in type 1 diabetes, and fenofibrate protects against non-proliferative retinopathy in type 2. What, a use for fenofibrate at last?

Lancet  31 Mar 2012  Vol 379
1199   Hard on the heels of the BMJ’s exposure of the harms of metal-on-metal hip replacements comes this damning analysis of the National Joint Registry of England and Wales. There has been a tremendous vogue for these devices, especially in young patients. It was thought that the larger the head, the better. Now the evidence has belatedly caught up with orthopaedic fashion, and the truth is devastating. Metal-on-metal devices should never have been licensed, and the bigger the head, the sooner they fail. The opposite is true of ceramic devices. Metal on polythene devices also work well. This is a scandal of regulation which could probably still happen—for all we know, it is happening as we speak, in some other area of the lucrative, virtually free-for-all market of medical devices.

1205   The Higher Calvinism of cardiology is a terrifying religious system of predestination by genomics. Someone needs to write a satirical novel about it, like James Hogg’s grim tale of Scottish Calvinism gone mad in Private Memoirs and Confessions of a Justified Sinner (1824). The latest focus of genomic theology is interleukin-6 receptor (IL6R) signalling, one of the many ways by which the wrathful gene-god dooms the unworthy to suffer cardiovascular disease. Never mind that we know many other important ways, and that this one is just an aspect of general inflammation. The Church of Genomics demands that we must not pit our humble understanding against a list of authors and investigators which covers two pages of small print. The entire priesthood proclaim that by analysing 82 studies, they can affirm that “large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.” Aye, consistent with. What more can the faithful believer require?

1214   The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium is a much smaller group—a mere 100 or so—but by combining the results of 40 studies in 133,449 individuals, it too concludes that “IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials.” Well, hold on. Most of us accept that inflammation plays a role in the ulceration of arterial plaque, and hence cardiovascular events. IL6R signalling is part of that process. It is also part of our inflammatory defence system, and perhaps a host of other things we don’t fully understand. In the editorial, we learn that large-scale trials of decidedly worrying agents such as methotrexate and canakinumab are already under way for vascular protection based on interleukin pathways. I just hope these guys know what they are doing. It will take more than a few “seems” and “consistent withs” to make me believe this mechanistic logic, however hard won.

1256   Have you run out of things to worry about? Fancy mongering a new disease? Try hyposelenaemia. The basis for selenium supplementation, according to this review, is that “low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline.” Alas, I am ignorant of my selenium status. I don’t even know my credit rating or my IQ. And I certainly shan’t rush to buy selenium from a “health” shop or online, because “supplementation of people who already have adequate intake with additional selenium might increase their risk of type-2 diabetes.” So why are these supplements on open sale? Shouldn’t we insist on a plasma selenium level first? Tell me, has anyone ever put “plasma Se” on a blood form?

BMJ  31 Mar 2012  Vol 344
Promoting exercise in sedentary patients is undoubtedly a worthwhile endeavour, but that does not mean we know how to do it effectively. A bit of exhortation now and again is unlikely to work, so the temptation is to refer patients elsewhere, and I have certainly written out lots of exercise prescriptions to local gyms. Unfortunately we don’t really know if this tactic works either. This systematic review from the Cambridge primary care department reaches a rather downbeat conclusion.

Florence Nightingale in the 1860s believed that hospitals were “an intermediate form of life,” dangerous to patients and soon to be superseded by teams of nurses who would look after sick people in their own homes. She really believed in the transfer of services to primary care, unlike most politicians who use it as a cynical excuse for disinvestment in hospitals. Hospitals in most places remain dangerous, inhumane environments: but absolutely irreplaceable, especially in the developing world. This survey of 26 hospitals from countries such as Egypt, Jordan, Kenya, Morocco, Tunisia, Sudan, South Africa and Yemen shows a high rate of potentially preventable patient harm. Mind you, so do many surveys of hospitals in rich countries. A study a couple of weeks ago showed that about half the hospital nurses in Europe would run away and do something else if they could. There is something about the culture of hospitals which needs hard work to repair.

Plant of the Week: Prunus avium

The wild cherry can be a pretty huge tree, growing to 25m high and across, and there is no finer spring sight than a fully grown one in flower. Its other names are supposedly the bird cherry, gean, or mazzard; but I have yet to hear an English villager exclaim “Why yon’s a glorious gean!” or “What a mighty mazzard that be!” though if I looked hard enough in the works of Thomas Hardy I might find such words.

It is the plant referred to in the lines of E A Housman, recited by every schoolchild of my period:

LOVELIEST of trees, the cherry now
Is hung with bloom along the bough,
And stands about the woodland ride
Wearing white for Eastertide.

Now, of my threescore years and ten,
Twenty will not come again,
And take from seventy springs a score,
It only leaves me fifty more.

And since to look at things in bloom
Fifty springs are little room,
About the woodlands I will go
To see the cherry hung with snow.

With only eight years left to go by Housman’s reckoning, I’d love to wander out into the woods of New England to admire the local cherry species – which are abundant, though smaller and less floriferous. But to save me time and effort, someone has planted the great European gean on my daily walk to work. It must be about 100 years old and it is entirely hung with snowy bloom this Eastertide. Loveliest of trees.

JAMA  21 Mar 2012  Vol 307
1161    When in Japan, do not attempt to drop down dead. In 800 fire stations around the Islands of the Sun, teams of emergency medical service personnel stand ready to rush out and perform resuscitation for out-of-hospital cardiac arrest, which cannot be discontinued until an ambulance arrives and you are taken to hospital, barely alive or truly dead. This non-randomized study of Japanese CPR shows that if the emergency team used epinephrine (adrenalin), your chance of having spontaneous circulation when you arrived in hospital would be 18.5%, and if they did not, it would be 5.7%. On the other hand, your chance of being alive at one month without major neurological impairment would be 1.4% if you had been given epinephrine, and 2.2% if you had not. So I think we can conclude that epinephrine should not be given during CPR. Next we need to find out whether out-of-hospital CPR should be given at all, since there is no firm evidence one way or the other.

1185   A lot of elderly people get deaf. Hearing aids can be useful, but this does not show up well in overall assessments of quality of life. Many deaf elderly people have other health problems which require a multidisciplinary team approach. I thought I’d tell you this in case you don’t have time to read this Clinician’s Corner piece, and didn’t already know.

NEJM  22 Mar 2012  Vol 366
1079   We’ve all been hoping for early wins in cancer genomics, but they are tantalizingly slow to arrive. With a few dazzling exceptions, cancer therapeutics moves through a painful grind of incremental progress. Here the investigators performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had acute myeloid leukaemia. They were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin, and the prognostic findings were compared with an independent set of 104 patients. Several gene loci were identified that predict response to this kind of treatment. And so the grind goes on: all credit to those who undertake it.

1090   And here’s a study of the Clonal Architecture of Secondary Acute Myeloid Leukaemia: more evidence that in cancer biology, complexity rules. Secondary AML is the kind that arises from myelodysplasia, and I can’t do better than quote from the abstract: “Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones.” In the new world of genomics, don’t look for simple mechanistic targets: look for fractal patterns, Fibonacci sequences, emergent properties, and all the other beautiful and dangerous things that make the crooked timber of humanity so interesting, and so hard to predict.

1099   The first trials of thrombolysis for stroke were carried out twenty years ago, but treatment with alteplase still occupies a marginal place in the everyday management of acute ischaemic stroke, despite efforts to encourage its use within the small window of benefit. But what if there were a thrombolytic agent that was nearly twice as good? This publicly funded Antipodean study compared two doses of tenecteplase with a standard dose of alteplase with just 25 carefully selected patients in each group. The higher dose of tenecteplase definitely produced the best results (72% v 40% disability-free at 90 days), but we need a bigger trial.

1108    When monoclonal antibodies were first produced, nearly 40 years ago, we were told to expect lots of magic bullets for a wide array of hitherto untreatable diseases. My whole working lifetime has passed by in those decades, and only a handful of my patients ever received treatment with a monoclonal antibody, usually with broad and unpredictable effects. High low-density lipoprotein cholesterol is a common biochemical finding, whether due to heritable causes or not. It is certainly associated with worse cardiovascular outcomes. So what might happen if we give people with raised LDL-C a monoclonal antibody to the enzyme which promotes LDL-C production? This enzyme is called proprotein convertase subtilisin/kexin 9 [PCSK9], but I don’t expect you to remember that. And the monoclonal antibody to PCSK9 is designated as REGN727/SAR236553 (REGN727), and I don’t expect you to remember that either. In fact I don’t expect you to remember anything about this study at all, except that the stuff reduced LDL-C levels in a few healthy volunteers and a few subjects with familial and non-familial hypercholesterolaemia, and did them no immediate harm. Or good. Now just keep this in the back of your mind, for the ten years of phase 2 and 3 trials that it will need to see if it’s safe and if it reduces events.

Lancet  24 Mar 2012  Vol 379
1103   According to the most recent post-mortem studies, the chances of a man of my age having localized prostate cancer are about 50-50. Whether it is detected or not depends on how many sharp instruments are repeatedly used to sample tissue via my rectum, which is why I am staying firmly seated. If I were truly worried, I think I would rather castrate myself, like some Early Father of the Church. Or I could take dutasteride, thus contributing to the profits of GlaxoSmithKline, who funded this trial and did most of the writing up. At three years the only difference I might notice would be an increased risk of sexual dysfunction. All other discernible outcomes would be much the same, but if I allowed the needle back up my rectum, less progression of my low-risk “cancer” might be found (hazard ratio 0.62, 95% CI 0.43-0.89). I am staying firmly seated, and I shan’t be asking my GP for dutasteride. Maybe just for lidocaine, in case I take the castration route.

1112   The nearest place to heaven on earth is New Zealand, but there is a serpent in this paradise (not literally: there are no snakes in New Zealand). There is guilt and inequality, even in this haven of non-violence and social progress. The white majority, descended mostly from British colonists of the nineteenth century, feel a legacy of bad conscience towards the Maori population, descended mainly from Polynesian colonists of the thirteenth century. Legend has it that all Maori people take their ancestry from just 13 individuals who survived the first journey in a boat that had lost its way. When British settlement began, they were deprived of much of their land by the Treaty of Waitangi, and barely survived extinction from European infectious diseases and economic domination over the next century. Born from fishers and hunter-gatherers, they have a “thrifty genotype” that helped them to get through times of famine, and their legends extol the low glycaemic diet of fish and moa meat that they kept to until white settlers arrived. This came just after the final extinction of the moa, a large flightless bird whose culinary qualities will remain legendary until someone manages to recreate it from surviving DNA. Clearly this is an urgent challenge for scientific gastronomy, but I digress. The point is that the Maori in New Zealand today, are showing increasing levels of hospital admission for acute infectious disease. Social deprivation and poor access to services play a part, and likewise their very high levels of obesity and hyperglycaemia, legacies of their ancestry in an age of abundant carbohydrates.

1142   “Large-scale randomised trials are urgently needed to inform how to best care for individuals with subclinical thyroid disease.” I would suggest that few things are less urgent than such trials on people with accidentally discovered borderline levels of TSH. But you may like to read this review and make up your own mind.

1155   Thyrotoxicosis on the other hand is definitely important, and it was the first diagnosis I ever made—at the age of 15 on the mother of a friend, who had a swollen neck and bulging eyes and shaky hands, like a description I had read in a chemistry textbook. She responded to surgery and carbimazole, and maybe radio-iodine. I don’t think there have been many advances in the 46 years since then, apart from beta-blockers for temporary symptom control: in fact this excellent review of the condition admits as much in its final paragraph.

BMJ  24 Mar 2012  Vol 344
I searched in vain for original research to inform your practice or your thinking in this week’s BMJ, but there is a gem of a piece by Lisa Schwartz and Steven Woloshin on the website, with the promise of more Not So Stories to come:

First an apology and retraction. Two weeks ago, I praised an MRC-funded study which claimed to show a clinically significant from continued use of donepezil or memantine in patients with moderate to advanced Alzheimer’s disease. Margaret McCartney pulled me up on this: although the study was conducted by good investigators and had no pharma funding, it still grossly overstated the significance and reliability of its results. These were tiny differences which would never be noticed by the patients (by definition) and scarcely by their carers, since the disease progresses inexorably whatever you do. If I had to fix a budget for my locality, I would rule out the use of these drugs in this population. And as soon as I return to the UK, I shall buy Margaret’s new book, The Patient Paradox: why sexed-up medicine is bad for your health.

But now to Steven and Lisa’s Not So Story. Re-enter donepezil, now off-patent at 10mg, but still patentable at 23mg for three years’ worth of lucrative sales, if only the U.S. Food and Drug Administration could be persuaded. There is actually a head-on study comparing the 10mg with the 23mg dose and showing no benefit and more adverse effects. So how did Eisai, the drug’s manufacturer, persuade the FDA to allow this formulation to be marketed? By the usual box of tricks—direct-to-public marketing, grossly misleading advertising to doctors, blatantly repeated on the labelling: all of which caused enough demand for the FDA to give way. Quis custodiet ipsos custodes?

The other good thing on the website is an editorial called “Putting Patients First.” A tired old cliché?  Maybe: but also the responsibility we carry now more than ever before, and the one thing that will save the NHS from the destruction willed upon it by politicians of every flavour. And this is a superbly written piece, arguing that everything we do should begin and end with the patient experience. Perhaps that is why it is behind the BMJ paywall, so that patients can’t read it and get ideas above their station.

Ann Intern Med  20 Mar 2012  Vol 156
405   Aha, here is the latest trial of a drug for type 2 diabetes, paid for by its manufacturers. This one is called Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Receiving High Doses of Insulin: A Randomized Trial. Now, what do you as a prescribing clinician need to know about the “long-term efficacy” of a drug which you will be discussing with your patient who has type 2 diabetes? Well, obviously it would be nice to know it if reduces the likelihood of cardiovascular events, blindness, renal failure etc. over a period of say ten years. Efficacy would imply that it is cost-effective compared to other treatment options. And what do we have here? A 24-week study showing that it reduces HbA1c and weight in some patients taking large doses of insulin. “However, this study could not evaluate long-term effectiveness and safety concerns that have hindered approval of this drug by the U.S. Food and Drug Administration” mourns the Annals summarist. Ah well, perhaps the FDA has its uses after all.

Plant of the Week: Magnolia cylindrica

The magnolias of New England are suddenly all out at once, as their flower buds have been irradiated by sunshine at temperatures of 25 degrees or more. The overwhelming favourites here as everywhere are M kobus var stellata and M x soulangeana. They are lovely and fragrant and always welcome at this time of year, but just a weeny bit boring.

The magnolia I always most desired, and possessed briefly, is the one known as “cylindrica (of gardens)”. The “of gardens” is a sniffy botanical term implying that this may not be exactly the plant first described by its discoverer – in this case no less than the greatest of plant hunters, E H Wilson of Chipping Norton. Though this is a beautiful plant both in flower and in seed, it is actually very rare in gardens—in fact I have never seen it in one, except in my own, which soon became its graveyard. So do try to find M cylindrica (of gardens), but when you do, prepare a luscious bed of well-rotted dung for it, and keep it away from limy material of any sort. Send me photos of its lovely white flowers with their pink bosses, and it bright red seed pods in autumn. I shall then regard you with gratitude, mixed with faint and friendly resentment.

JAMA  14 Mar 2012  Vol 307
1029   The Viewpoint pieces in JAMA this week are a strange mix of fact and fantasy. The first is a piece about industry payments to physicians and teaching hospitals in the USA. I am currently at Yale University alongside the authors of this piece, one of whom is a good friend. I am observing the US health system at first hand, so I can tell you what is coming to the NHS. You think it’s bad enough that private firms are already buying up NHS hospitals and child health services? You ain’t seen nothing yet. The whole of the American health system is saturated with the influence of the pharmaceutical and medical devices industry: huge payments are made directly to individuals or institutions to influence purchasing decisions. In the UK, we call this corruption, but only for the time being: look at those lists of payments to our MPs from private health providers published in the Daily Mail, of all places. No wonder our legislators are baffled by all the opposition they are facing from British doctors as they try to open up our antiquated socialist NHS to the healing influences of unbridled capitalism. Come on all you GPs who will be running NHS plc—there is money to be made by everybody! In America there is due to be public listing of all such payments in 2013. I wonder if it will make any difference. It is wonderful how much public disquiet people can handle when they have a few million in the bank.

1031    The next piece argues that everything will nonetheless be all right in the end, because genomics will come to the rescue. There is a technical fix for everything, and industry is smart enough to find it. Look, the cost of genomic profiling is falling all the time! Soon we will be able to treat fewer people because their DNA will tell us whether the drugs will work or not. And of course we will produce all sorts of better targeted drugs. It’s just a shame that they mostly cost $10K per month at present. But all this is bound to change, provided we look to the gleaming towers of lucrative science and ignore the ubiquitous realities of poverty and old age.

1033   And we must do more to prevent depression. The main reasons given in this paper are little to do with the misery of individuals but the misery that they may spread to others by being so miserable, and their effect on economic productivity. We must be on the look-out for people who do not smile enough, i.e. those with “subsyndromal symptoms”:  “Methods with proven effectiveness involve educational, psychotherapeutic, pharmacological, lifestyle, and nutritional interventions… The use of booster sessions and Internet technologies should be explored.” This sounds like a great idea. Pretty well everyone has pre-depression and if everybody gave each other encouragement, education, a good lifestyle and good nutrition we would all be happier. This used to be called the welfare state. But obviously it’s better to trap people in a hopeless cycle of debt and work (or lack of it) and then bring in private counsellors to address their pre-depression issues, and give them serotonin reuptake inhibitors.

1037   Every now and again, Canada is held up as an example of how to provide good healthcare. In fact, last week JAMA daringly had a Canadian advise the USA on how to set up a better health system. So, does the experience of Canada tell us that we should attempt to provide better care by reducing hospital staffing and costs? Well, actually, it tells us the very opposite. Mortality and readmission rates were lowest in hospitals with the highest costs and levels of spending. Canada works with a system of private providers. So if we want to improve the NHS, we should bring in private competition, and if we want good care we should purchase it from the providers with the highest costs. Or if we want rubbish care, we should buy if from the lowest bidder. This will be the responsibility of all GPs acting on behalf of their patients. You know it makes sense.

1072   Does This Patient Have a Severe Upper Gastrointestinal Bleed? My pre-test probability is high. I am an old man taking low dose aspirin, driven to dyspepsia by the thought of the undemocratic destruction of the NHS, seized with griping upper abdominal pain whenever I hear the words “Liberal Democrat.” I will spare you a description of my stools. Though this would be vital in the clinical situation, and might save me from a rectal examination in the emergency department. Here is a first-rate contribution to the first-rate Rational Clinical Examination series: “Melena, nasogastric lavage with blood or coffee grounds, or serum urea nitrogen:creatinine ratio of more than 30 increase the likelihood of a UGIB. (NB: Why don’t we have this in the UK?) The Blatchford clinical prediction score, which does not require nasogastric lavage, is very efficient for identifying patients who do not require urgent intervention.” The Blatchford score was devised in Glasgow (by a GP, amongst others) but the original Lancet paper from 2000 is still behind an Elsevier paywall. But you can get the score on Wikipedia. Everyone should work to make Wikipedia the foremost reliable source of medical information, and to make the Elsevier business model a thing of the past. This won’t help to save the NHS, but at least it will help to get knowledge out where it is most needed, i.e. the resource-poor world.

NEJM  15 March 2012  Vol 366
981   Here is the screening paradox summed up in a single study. The European Randomized Study of Screening for Prostate Cancer used prostate specific antigen—often called PSA because it has Perfectly Stupid Attributes for a screening test. Nonetheless, in this 11-year follow-up study, the risk of death from prostate cancer was lowered by 21-29%. But all-cause mortality did not differ between groups. Amazingly, I have seen this declared a success for PSA screening in some of the American medical press. Now clearly, if you don’t mind what goes on your death certificate, prostate screening is a waste of time. But to inform our advice to patients, let’s look at it from the perspective of somebody who had decided they would rather die of anything but prostate cancer. “To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected.” So if you had a “cancer” detected by screening, there is a one-in-37 chance that treatment would prevent your death within 11 years. And your odds of dying from anything in that period would be the same.

991    In my last year as a proper GP, I presented two cases from my practice of young women who had suffered cryptogenic stroke and had been found to have patent foramen ovale. OK, foramina ovales. I gathered together myself and a GP partner and a local stroke doctor and some interventional cardiologists from Oxford, and we had a high old time congratulating ourselves on our diagnostic acumen while the receptive audience admired real-patient videos showing the technical wizardry of percutaneous PFO closure. Clearly, we had saved these ladies from the dangers of recurrent stroke by the timely deployment of sophisticated interventions based on impeccable mechanistic insight. But even during the presentation, there was a slight feeling of unease when the evidence base for this presumption was interrogated: PFOs can be found in 25% of the population and there didn’t seem to be an adequately powered study to compare device closure of PFOs with medical therapy. Well, now there is, with a follow-up period of two years, and there is no difference in outcomes so far. So while I was trying for one last time to share some of the glamour of sophisticated sexy medicine, perhaps all that these patients needed was what I had tried to provide them with for the whole of my working life—good primary care.

1000   Another week, another study of a new oral treatment for relapsing-remitting multiple sclerosis. This one is called laquinimod, and as far as I can tell it is about the same as all the others—it produces a modest decrease in the rate of relapses and a 4.6% absolute decrease in progressive disability over two years. The study was placebo-controlled and conducted at 139 sites in 24 countries. It was paid for, designed, and analysed by Teva Pharmaceutical Industries, and the paper was written with help of an external writing agency. There seems no obvious reason why laquinimod should not now be licensed for use in MS at a cost similar to that of other novel agents, even though we know little about its long-term harms or benefits or how it compares head-on with these other treatments. We demand very little from our licensing agencies before drugs like these can be tested on patient populations. Patients are seldom told they are being used experimentally, doctors have no real means to judge their place in therapy, and meanwhile drug companies can get rich on what they charge for them. Maybe we are all fine with this as a business model: if we are so used to it, it must be right.

1010   Ingenol mebutate is a really neat treatment for actinic keratosis: four RCTs show that it works with 2-3 applications. It’s made from the sap of Euphorbia peplus, the petty spurge which is abundant in many parts of north America. It is doubtless very cheap for Leo pharmaceuticals to produce, and with such a tiny quantity needed for such a brief duration of treatment, perhaps they are thinking of giving the stuff away. Well, actually, one website quotes $699 for 141gm of 0.015% ingenol gel. But don’t be tempted to save money and find some petty spurge to put on your keratoses: the sap can burn quite badly.

Lancet  17 Mar 2012  Vol 379
1005    The National Patient Agency has surveyed mental health services in the UK from 1997-2006 to see if there is a relationship between suicide rates and implementation of recommendations to prevent suicide issued by the National Confidential Inquiry. These recommendations include such things as the formation of 24 hour crisis teams and assertive outreach groups for vulnerable patients who are poor attenders of conventional services. People who have both depression and alcohol problems, and are thus at highest risk for suicide, are no longer supposed to be pushed back and forth between services designed for one or the other problem but never both. By and large, the study finds a correlation between the degree of implementation of the recommendations and a fall in suicides. It isn’t the ultimate in scientific rigour, but it makes sense. Like all mental health provision in the NHS, it is a rather bleak minimum.

1045   Since serotonin reuptake inhibitors came on the scene, suicide rates have fallen in most countries. Is this cause and effect? There is no methodology which can possibly answer that question, but at any rate it makes it unlikely that they cause increases in suicidal behaviour at a population level. There was one large study of males in the USA which seemed to show that sertraline reduced suicidal behaviour compared to other antidepressants, or none. You can find this and other bits and pieces of information in this review of major depressive disorder: new clinical, neurobiological, and treatment perspectives. There is a convincing mechanistic biochemical explanation for every drug that works for depression, and for every one that has been tried and failed. All the time, extremely clever people are discovering more about the neurobiology of the depressed brain. This article discusses dozens of new pathways we could tinker with. Whether this would produce any results that are better than chance alone, nobody can tell.

BMJ  17 Mar 2012  Vol 344
I haven’t been able to access Latest Print Version on the BMJ website for several days, so I have picked a couple of research papers out of the Last 7 Days section.

There’s a general feeling that we don’t have enough good drugs for type 2 diabetes, and it’s hard to argue otherwise. So we should extend a welcome to any new drug that helps to lower blood sugar, especially if it doesn’t cause weight gain or hypoglycaemia, right? I’m ashamed to say that until about three years ago I would have nodded in assent. I may even have prescribed a few patients a dipeptidyl peptidase-4 inhibitor (or gliptin) just to show how up to date I could be. But what I was doing was performing an unwarranted human experiment, since we have no idea whether these drugs do more harm than good in the long term. A drop of one point in HbA1c is rarely worth the risk, especially if you don’t know what the risk is. This meta-analysis hedges its bets, as it must. But betting in the dark with the long term future of patients is not a good thing to do, ever.

But perhaps there is a subgroup of diabetic patients who are particularly likely to benefit from treatment with a gliptin, the drug rep or the paid lecturer might argue. Look, in this trial (he says, handing you the reprint), patients with red hair showed a much bigger drop in blood sugar, and moreover their LDL-cholesterol levels were halved. Here are some nice pens and do help yourself to the delicious sandwiches. With Wondagliptin you may be able to meet all your targets for red-headed diabetics, and we can help train your practice nurse to do it with the aid of daily blood glucose monitoring. Do I exaggerate? Not much, I fear. Anyway, back to subgroup analyses. Don’t believe them, especially in industry-funded studies. If you are an EBM nerd, or even if you are not, it is worth looking at this systematic review of the credibility of subgroup claims in randomised controlled trials.

Arch Intern Med  12 Mar 2012  Vol 172
397   About ten years ago, I advised you to train your larynx to pronounce the word ximelagatran, the name of the first direct thrombin inhibitor which seemed poised to replace warfarin for numerous clinical indications. If you followed my advice, you abraded your vocal cords and twisted your palate to no avail, since the drug was withdrawn in 2006 following reports of hepatotoxicity. Its successor dabigatran is easier to pronounce, works well at a fixed dose, and generally seems harmless to the liver. Boehringer Ingelheim seemed to have a winner on its hands. But alas, a cloud no bigger than a man’s hand has appeared on the horizon. Here is a meta-analysis which shows that dabigatran is associated with an increased risk of MI or ACS in a broad spectrum of patients when tested against different controls, and that is not something one likes to hear about a drug designed for long term thromboprophylaxis.

Plant of the Week: Euphorbia amygdaloides var robbiae

Like all members of the spurge family, this one seeps toxic sap, though whether it contains ingenol I have no idea. You could make your fortune by finding out. After all, it is a wood spurge that likes to grow in dark places, so its juices are bound to work for something that is caused by sun damage. Or does it work the other way round? I lack grounding in the science of herbalism.

This handsome plant bears the somewhat dismissive label of “excellent for ground cover.” All winter long, you have ignored its handsome rosettes of dark leaf, except perhaps on some magical sunny day when they have shone with a covering of frost. Now, as the ground warms, it is sprouting great flower-shoots of pale fresh green. Soon it will go back to its usual job of growing where nothing else will, and sometimes where you don’t want it to. Excellent for ground cover, indeed, and lovely in early spring.

JAMA  7 Mar 2012  Vol 307
915   “Almost 2 and a half million people in the United States die every year, making death the most common health event in the United States” says Mary Tinetti in a Viewpoint piece called The Retreat from Advanced Care Planning. It’s a strange and somewhat disturbing choice of words, but then Mary is feeling somewhat disturbed. “In the months after the death panel uproar, family members of 2 patients accused me of being part of a government-backed plan to save money by not offering expensive care to frail older patients.” Instead, she wanted to talk about the kind of care that was humane and appropriate in the light of the common health event the patient was facing, i.e. death. So a moronic scare campaign dreamt up by Sarah Palin to undermine Obama’s Affordable Care Act has ended with patients and families being unable to discuss appropriate end-of-life care, and one of America’s foremost advocates for the elderly admitting that “These experiences left me feeling attacked and frankly reluctant to continue an activity that is the core of my responsibility as a physician.” God Bless America.

922   A couple of years ago, The Lancet published a case series by an eminent neurosurgeon from Queen Square reporting his superb results with surgery for epilepsy, with most of his patients cured after many years of fits (mostly temporal lobe) which were resistant to multiple medication. Here we have another bit of evidence that temporal lobe epilepsy surgery works – and again it’s not a proper, fully powered randomised controlled trial, but a study that was half-completed due to recruitment problems. These trials may not fit into the highest levels of the EBM hierarchy, but the figures here tell their own story: no complete seizure control in the non-surgical group (23), compared with 11 out of 15 seizure-free two years after surgery. No p-values needed.

NEJM  8 Mar 2012  Vol 366
883   The original title of the most famous text in biology was On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. The one thing that Charles Darwin could not explain in 1859 was how “favoured races” came to acquire their favourable characteristics. He could draw up a phylogenetic tree showing branching evolution, but until the coming of Mendelian genetics and the unravelling of the structure of DNA, nobody could explain exactly how this could operate through the processes of sexual reproduction. In fact it is much easier to observe at the level of asexual reproduction, in single-celled organisms like bacteria – or cancer cells. This ground-breaking British study traces the evolution of renal carcinomas using DNA analysis from the primary tumour site and various metastases. And what emerges is – you nearly guessed it – a phylogenetic tree showing branching evolution for each tumour line, as tumour DNA changes through furious cycles of unregulated division. This in turn means that any single tumour sample will not necessarily reflect the DNA of the cancer as a whole. The ideal of genomic analysis leading to personalized cancer cures gets a reality check when faced with this awesome demonstration of complex adaptive biology at work. Magic bullets will need to hit multiple targets at once: as these brilliant investigators drily remark, cancer heterogeneity “may present major challenges to personalized-medicine and biomarker development.”

893    And now for some more good British science supported by the MRC: The Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO) study. This was a multicentre, double-blind, placebo-controlled, clinical trial with a two-by-two factorial design. Most of us have long suspected that these drugs have no clinically meaningful effect on progression in Alzheimer’s disease and are largely a waste of money. Well, this trial proves us wrong. Even in patients as far gone as this, with Mini-Mental State scores between 5 and 13, both donepezil and memantine definitely slowed progression when continued, though combining the two had no additional effect. This study and the one before make it a great week for the UK Medical Research Council: glasses of best English sparkling wine should be raised throughout its premises.

925    Ever heard of the word abscopal? It sounds like some obscure ecclesiastical usage – a bishop performs abscopal ordinations outside his diocese, perhaps. Well, in oncology, it refers to the effect of a treatment at one site on metastases elsewhere. Specifically, we are told, “The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system.” Neat, and useful. This paper describes the case of a young woman with metastatic melanoma who received treatment with ipilimumab. This wasn’t achieving much until she had radiotherapy to a paraspinal mass. Thereupon all her other metastases started shrinking. Four years from the first discovery of metastatic disease, she remains stable on ipilimumab. Let us hope that abscopy proves to be a useful new direction in cancer treatment.

932    Which muscular organ is constantly active from birth to death, sustaining life without our commonly being aware of it? The QI hooter will go off if you answer the heart, although you will be technically correct, of course. But the structure I am referring to here is actually the diaphragm. There is never a week in these medical journals where heart disease is not mentioned, but I think this is the first article I have ever encountered on dysfunction of the diaphragm. We really do take our vital bellows for granted. The fact that we can is testimony to the diaphragm’s stolid efficiency in most conditions – except those rather rare and extreme ones described in this article, which I mainly mention for its value as a rarity.

(Someone should write an Ode to the Diaphragm, beginning,
Lo, thus I breathe!
Therefore I am!
Let us extol the Diaphragm!
That with its soft unnoticed thrusts
Sustains our life by vital gusts.)

Lancet  10 Mar 2012  Vol 379
895   “The Lancet, you may have noticed, is a seriously weird journal. One of the things it likes to do is publish the results of cutting-edge human experiments before they have any clear outcomes” I wrote here two weeks ago. This hasn’t changed in a fortnight, and in fact it hasn’t changed in over a decade. During this time there have been lots of small trials of stem cells for repairing myocardium: these were novel and exciting to begin with, but you might be forgiven for wanting some evidence of actual benefit by now. Here in the latest phase 1 trial, CADUCEUS, the stem cells were cardiosphere-derived, i.e. grown from the patients’ own cardiomyocytes obtained by endocardial muscle biopsy. Cultured autologous precursor cells were introduced by coronary artery infusion, and at six months there was MRI evidence of scar repair and new myocardium but no change in functional indices at all. There will now be a phase 2 trial. Can’t wait. You may want to read more about what hasn’t yet happened in this field in the review article, towards regenerative therapy for cardiac disease.

905    In the days when I was still a proper doctor with a consulting room of my own, I used to shock and confuse visiting health professionals by keeping a mercury sphygmomanometer with an adult cuff that covered 80% of the upper arm. That way I could at least believe my own blood pressure readings. I even tried to keep abreast of the hypertension literature for a while, since it seemed best to know something about the commonest reason for treating healthy people in primary care. And I even uncovered the odd case of primary hyperaldosteronism. But I very rarely measured the BP in both arms, except in one memorable lady with a cold hand and a loud subclavian murmur, who provided my one and only diagnosis of subclavian stenosis. Here is a frustrating systematic review of the difference in BP between arms and vascular disease and mortality – frustrating because it doesn’t place its findings in any useful context. In particular there is a digression about the ankle/brachial pressure index without a direct comparison with the arm/arm BP index, but without clarifying which is more useful in which clinical situations. The authors are willing to commit no further than some mights and coulds: “A difference in SBP of 10 mm Hg or more, or of 15 mm Hg or more, between arms might help to identify patients who need further vascular assessment. A difference of 15 mm Hg or more could be a useful indicator of risk of vascular disease and death.”

BMJ  10 Mar 2012  Vol 344
The latest and best meta-analysis of randomised trials of self monitoring of blood glucose in people with non-insulin treated type 2 diabetes uses individual patient data to show once again that use of this expensive technology does not lead to any clinically meaningful improvement in glycaemic control. It’s high time that guidelines such as NICE reflected this. We encouraged this practice once, in the belief that it would help patients manage their condition better. Then it became a lucrative scam for the test strip manufacturers who could change their systems every few years to ratchet up costs which are borne by the NHS. Now it’s time for a reality check, and for some serious questions about futile spending to be addressed.

I’m not a great fan of modelling and simulation and cost-effectiveness studies, though these seem very popular with the BMJ. I like things that I can understand and interrogate. Still, I was rather intrigued by the notion of a Dutch microsimulation model. Does it contain little dykes and windmills and adjust for cannabis use? Prosaically, it is merely based on Dutch cervical screening data, and it reaches a conclusion that I have been wanting to hear from some time – most European countries should consider switching from primary cytology to HPV screening for cervical cancer. But still, Nullius in Verba – the Royal Society motto which roughly means “don’t take their word for it.” Anything which requires specialist software, Dutch or otherwise, can only be taken on trust.

In 1991, my practice took on a brilliant new partner who was a paediatrician with a special interest in asthma. I can remember saying to him at interview, “Oh good, we need you to sort out the mess which is childhood asthma.” In those days, not only did every child who had ever wheezed get the asthma label for life, but also every child who coughed for more than a month, especially at night. Nowadays we distinguish – as we easily could then, if only we had been given official permission to – between pre-school wheezing, post-infective wheezing, atopic asthma, post-infective cough and chronic cough in children. Here at last is a practical review of the last topic which plainly states that “Isolated cough without wheeze or breathlessness is rarely caused by asthma”. Some time ago, our practice took part in a study by Anthony Harnden which showed that up to 25% of persistent cough in children and adults is associated with evidence of recent pertussis infection, but most people still seem to be unaware of this. There is nothing to be done but wait it out, anyway. For other diagnostic possibilities, and sensible management advice, keep this article.

Ann Intern Med  6 Mar 2012  Vol 156
329    A simple and outstandingly useful Dutch RCT demonstrates clearly that early treatment of rheumatoid arthritis with methotrexate and prednisone 10mg daily is superior to methotrexate alone. The primary end-point was erosive joint damage at 2 years. But combination treatment was also superior for minimizing the need for DMARD and biological drugs, and caused fewer adverse effects.

340    Lisa Schwartz and Steve Woloshin have tirelessly striven for over a decade to help people understand how to interpret basic medical numbers and concepts. Some of their effort has been directed at patients, some at the general public, some specifically at journalists, and some at doctors. In this classic study they and two colleagues look at how well American primary care doctors understand cancer screening statistics. The news is worse than you could have believed. “When presented with irrelevant evidence, 69% of physicians recommended the test, compared with 23% when presented with relevant evidence (P < 0.001). When asked general knowledge questions about screening statistics, many physicians did not distinguish between irrelevant and relevant screening evidence; 76% versus 81%, respectively, stated that each of these statistics proves that screening saves lives (P = 0.39).” Aargh.

360   The previous study is not by any means the only one to show that doctors can be very poor at handling numerical data; there have been lots of studies in patients too, and some in surrogate decision makers. Here is a mixed-methods (hurray!) study of how relatives and decision-making carers of people incapacitated by serious disease interpret prognostic information, whether given as numbers or words. Such discussions usually take place in the context of continuing life-supporting treatment, so this could hardly be less trivial. And the investigators find that misunderstanding is rife – and tends to be in one direction only, so that it is not simply misunderstanding but cognitive bias towards optimistic interpretation.

Plant of the Week: Helleborus x ericsmithii

As the growing season begins to unfold its delights, the plants I most look forward to are the hellebores. Alas, I have found none so far in New Haven, perhaps because the soil is lime-free and unfavourable to the whole genus. Or perhaps it has been too cold so far. Back in England, our garden must be awash with self-sown oriental hellebores with their perfect flowers of white, black, pink and yellow, spotted or otherwise – or intriguing dull green, as in the amusing cultivar “Old Ugly”.

We also miss the chance to buy new hellebores, which must be done while they are in flower, and from a specialist nursery with a decent choice. I would like at least to see the one named for the greatest of hellebore fanciers gone by, Eric Smith. It has leaves of veined pewter with long flower-stems bearing white flowers with a hint of pink. I think if I saw it I would buy it. I might have already. That’s the nice thing about old age, as Ronald Reagan remarked.

NEJM  1 Mar 2012  Vol 366
777   There is no JAMA this week, and the best things in the New England Journal come right at the start. Whether you are a British GP contemplating another set of humiliating idiotic directives and the imminent destruction of the NHS, or an American physician wondering how your crazy health system can ever be turned into something rational and sustainable, or an academic wondering how much more futile research you have to grind your way through and pretend to be interested in, here is the boost you need. Goal-Oriented Patient Care — An Alternative Health Outcomes Paradigm. For the battle-weary GP, an affirmation of the central value of what you came into medicine to do – to help patients to achieve goals that they choose for themselves, in a continuing dialogue about the possible and the practical. For the American system, a model of care that puts the patient at the centre and emphasizes joined-up, affordable care. For the academic, a new research agenda based on what will best inform shared decision-making with patients and society. Download this article by David Reuben and Mary Tinetti at once and keep it under your pillow.

The NEJM lets you have this free, and also the companion pieces which follow – about shared decision-making and defining patient-centred care. Both good, but the Reuben/Tinetti is a gem.

787   Now back to the bizarre world of the medical-industrial complex and the way that it generates “evidence,” and large amounts of money, with the help of medical journals. Ruxolitinib is an inhibitor of Janus kinase (JAK) 1 and 2, and it costs about $85,000 for a year’s treatment. Here are two new trials of ruxolitinib in myelofibrosis, showing some symptomatic benefit, but no survival benefit compared with best available therapy. Myelofibrosis can’t be a particularly rare condition, since I have encountered it several times among the elderly patients of the little flock I once used to shepherd. Once you have it, you will probably die as a result: which is a pity, but then we all have to die of something in old age. So symptomatic benefit is a laudable goal. But how do you go about setting that against costs of this order? The editorial explains a bit more about the issues at stake, but points out that these studies add little to what an NEJM long-term study had shown a few months ago. It concludes: “Approximately 30% of patients with myelofibrosis present with ruxolitinib-sensitive symptoms, and the drug might be useful in a fraction of these patients who are not candidates for allogeneic stem-cell therapy or for clinical trials of potentially better drugs, including newer and more selective JAK inhibitors.” So what are these papers doing taking up prime-time space in the world’s leading medical journal?

808   Here’s a UK trial of nicotine replacement patches to reduce smoking in pregnancy. If this were a pharma-funded trial hoping to sell nicotine patches, we might expect it to have been conducted in 76 centres in 15 countries, but instead this government-funded study recruited from 7 antenatal clinics in the West Midlands, and still managed to be 4 times larger than any previous trial. Unfortunately, though, it showed the same result as all the others: that nicotine replacement in pregnancy has no effect on overall cessation rates.

Lancet  3 Mar 2012  Vol 379
815   The Lancet is back on one of its frequent excursions into China: small recompense from our clapped-out little island which once tried to destroy Chinese civilization by forcing its population to become opium-dependent and then strangling its trade. Alas, the imperialism of bad ideas continues. Western notions of chronic kidney disease have now bestowed silent ill-health on 120 million Chinese people, whose creatinine clearance is dangerously below 60mL/min per 1.73m2, or who have albumin in a single sample. What is to be done? Absolutely nothing, of course. The Chinese health system has far better things to concern itself with, as the preceding article on health coverage and catastrophic expenditure makes clear.

823   Another bad Western idea is that adverse prognostic markers are somehow valuable. If you happen to have had surgery for non-squamous, non-small-cell lung cancer, you can now undergo a practical molecular assay to predict survival, thanks to the efforts of a Chinese team. When pressed, researchers who uncover these harbingers of doom generally claim that they identify a subgroup of patients who deserve special further investigation, or closer clinical follow-up. But in fact all that this test will tell you is whether are likely to snuff it, which is rarely a comforting or useful thing to know.

833   “The pace of reform should be moderated to allow service providers to develop absorptive capacity. Independent, outcome-based monitoring and evaluation by a third-party are essential for mid-course correction of the plans and to make officials and providers accountable.” This is the conclusion of an examination of China’s huge and complex healthcare reforms. I suggest that we should send Andrew Lansley and David Cameron on a fact-finding mission to China. Three years should do it.

BMJ  3 Mar 2012  Vol 344
Here’s a fact we would rather not face: we cannot really know the safety of devices or drugs over long periods of time unless we test them over similar periods of time. It is certainly not a fact that drugs and devices manufacturers want to face, and more worryingly it is something that regulatory agencies are very poor at addressing on our behalf (see the account of European and US device regulation in NEJM). The bar for introducing new devices is set very low, and once the device is over the bar, post-marketing surveillance is often nugatory. If you think this doesn’t concern you, then you must be somebody who has never referred a patient for hip replacement. Metal-on-metal hip prostheses have become hugely popular in the last two decades, and metal resurfacing of the hip is a great British invention in the best Barnes Wallis tradition, perfected by an orthopaedic surgeon rolling his sleeves up and tinkering with cobalt and chromium in his garden shed. Deb Cohen’s piece tells it all. So do we really want to face the fact that these devices spread metal ions and particulate matter all over the body, with some obvious harms and others we do not know? Should we insist on a 15-year testing period for all permanent implantable devices? Or should we ignore such uncomfortable facts, and just carry on with a system which supports the great medical devices industry and harms patients?

Acute cannabis consumption and motor vehicle collision risk. A meta-analysis, pointing out that you should not drive if you are stoned, just in case you kill somebody.

It was nice of the BMJ to publish this paper led by two physiotherapy PhD students from Sweden, but it would have been better to wait until they had some useful data. It was a 12-week study examining subacromial impingement syndrome. The right kind of exercise helps to avoid surgery during this time period. Aha. And then?

“Profiles for psychological, vasomotor, and sexual discomfort symptoms relative to age at menopause could help health professionals to tailor their advice for women with natural menopause” claim the authors of this study. I’m not entirely sure what the advice might be. Generally it is better to move up social classes as much as possible, and also to get a degree, but only if you do this in your 20s rather than your 50s. Don’t marry if you want to avoid late menopausal symptoms. But nobody has done a randomised controlled trial of divorce for symptom control (blinding would be only one of many problems). In all, the main value of this study is to characterize a number of discrete patterns in menopausal symptoms, rather than identify any modifiable factors.

The Uncertainties Page this week has a nice account of the evidence around the use of probiotics to prevent antibiotic-associated diarrhoea. If your patient has ever had diarrhoea associated with antibiotics before, probiotics are certainly worth advising. It may be going too far to recommend their routine use by all healthy individuals taking antibiotics, but then Greek yoghourt is nice to eat anyway.

Arch Intern Med  27 Feb 2012  Vol 172
312   Doctors and patients love to share simple mechanistic explanations of diseases and cures. Angina pectoris is caused by blocked pipes: unblock the pipes, preferably leaving behind something to keep them open, and you have cured the problem; whereas if you just keep on pushing tablets, you’re just treating the symptoms without dealing with the cause. Most of us shared this belief with cardiologists and with patients, until the COURAGE trial came along in 2007 to prove otherwise (and the trial was nearly never done because many interventional cardiologists considered it unethical). This meta-analysis looks at this and 7 other trials and confirms the counter-intuitive conclusion that “Initial stent implantation for stable CAD shows no evidence of benefit compared with initial medical therapy for prevention of death, nonfatal MI, unplanned revascularization, or angina.” Collusion in mechanistic certainty is one of the great barriers to progress in medicine, and it may cause direct harm to patients, as the next paper illustrates.

There isn’t much else of note in this week’s printed Archives, but hidden in the Online First section awaiting paper publication is a remarkable study of patient satisfaction in relation to outcomes. This is worth spending some time on. In the USA, the highest quartile of patient satisfaction is associated with 9% higher  inpatient care and drug costs, and – wait for it – 26% higher mortality. What is killing America’s most satisfied patients? Is there some hidden confounding here (as the editorial hints)? The authors adjust for everything obvious, such as age and health status; so perhaps the kind of medicine these patients are getting really is 26% more dangerous. But this exceeds even the most pessimistic predictions of those of us who have long held that the overprovision that American patients are programmed to demand might be dangerous. Costly, futile, yes: but as lethal as this? I intend to spend an hour with my brilliant group of young overseas doctors at Yale picking over this paper. If nothing else, it will have some lessons on what to avoid in their own health systems. I firmly believe that all health provision should be judged by the experience of patients, but the simple criterion of fulfilled expectation is clearly inadequate, and may be positively dangerous in societies which ratchet up demand for medical services while ignoring costs and harms.

The same set of Online First papers includes a Research Letter from the UK which is relatively reassuring about the value of patient opinion, at any rate about hospital in-patient episodes. British patients have been encouraged to rate their experiences of all 166 acute NHS hospitals on the NHS Choices website. When compared with routinely gathered measures of clinical outcome and hospital-acquired infection, patient opinion showed a high degree of correlation with quality.

Plant of the Week: Hamamellis mollis

We can’t grow witch-hazels on the limy clay of our garden at home, but here in New Haven they thrive on the local acid sand. Many of the colleges have planted them in borders by the road, and they don’t seem to mind fairly high levels of motor exhaust. Passers-by in late winter are hit by a sudden wall of spicy scent, and become aware that these medium sized shrubs are covered in thin tassel-heads of dark yellow or (in other species) dull red. Older, larger specimens make a fine sight beneath the blue skies we sometimes enjoy here.

Hamamellis mollis is really a small tree, so you might do better to look for H japonica or the hybrid of the two, called H x intermedia, which comes in colours ranging from pale straw to dark brick. The yellow ones tend to have the most scent. Also, if you happen to have bleeding piles that require immediate attention, you can rush out and use the bark or leaves as an astringent.

JAMA  22 Feb 2012  Vol 307
813    When an Italian team of physicists reported that they had detected neutrinos travelling faster than light, the televisual physicist Jim Al-Khalili promised to eat his boxer shorts if it proved to be true. It turns out to have been a measurement error due to faulty wiring. Unbelievable results either shatter the laws of the known universe, or else they are wrong. So if a study tells us that 42% of women and 31% of men presenting with myocardial infarction do not have chest pain (or even pain in the arm or jaw), this either overturns clinical medicine as we know it – from experience and from several other large cohort studies – or else it is due to lousy recording. Guess which. This retrospective study is based on a single tick in a box completed by busy physicians looking after over a million patients coming into American hospitals with heart attacks between 1994 and 2006. It could be that they had better things to do than record the obvious. If these figures are true, then I will eat my elegant black Marks & Spencer long johns. These thermal underpants have proved very effective at protecting my lower parts from the ravages of winter on the eastern seaboard of America, and I just wish journal editors were as effective at protecting us against the ravages of bad data.

823   It’s a while since I was a proper GP, with a consulting room of my own and an obligation to endure baby clinics every so many weeks. As a result, I’ve completely lost track of what the standard infant immunization schedule now is in the UK. The poor mites seem to suffer an ever-increasing bombardment of antigens, but I no longer have to listen to them squawk somewhere down the corridor. So I will leave it to you to judge whether you need to know that “DTaP-IPV-Hib vaccination was associated with an increased risk of febrile seizures on the day of the first 2 vaccinations given at 3 and 5 months, although the absolute risk was small. Vaccination with DTaP-IPV-Hib was not associated with an increased risk of epilepsy.”

832    There was once an editorial in Gut which began, “The liver is a stupid organ. It can only grunt.” The point that this witty hepatologist was making is that estimating liver health from enzymes and ultrasound is like taking a history from a pig. Veterinary experts can no doubt pick up some diagnostic clues from the noises of their porcine clients, but it probably goes little beyond “oh dear, something’s the matter.” In this paper, the Rational Examination series revisits the question Does This Patient With Liver Disease Have Cirrhosis? In the best tradition of this generally wonderful series, 86 studies of patients referred to liver clinics are analysed in great detail and the findings are written up clearly and comprehensively. Astonishingly, alcohol history has no useful predictive value. The gold standard is liver biopsy, though even this can miss its target. All in all, this is a great contribution to the science of gruntology, but the end result is just a better kind of guessing.

NEJM  23 Feb 2012  Vol 366
687    This long-term report from the National Polyp Study made newspaper headlines the world over, which just shows that if you do lots of colonoscopies to remove colorectal adenomas for a period of up to 23 years, you may eventually get your 15 minutes of fame. More importantly, those you have treated will have half the rate of colorectal cancer of the general population. Since they were at greatly increased risk to start with, this is quite an achievement, and shows that a single colonoscopy per lifetime might reduce the population rate of colorectal cancer by up to 53%.

697    But the next paper brings us down to earth. A randomised non-inferiority trial of once-only colonoscopic screening compared with faecal immunochemical testing every two years has been going on in 8 regions of Spain since 2008. It seems that Spaniards are no different from the rest of us in their aversion to collecting poo (34.2% uptake) or having lengthy instruments introduced into their bottoms (24.6% uptake). The preliminary results seem to show a similar detection rate of cancers using the two methods, but a much higher rate of adenoma detection with colonoscopy. How to make screening more acceptable is the fundamental (sic) problem.

707    For patients with disseminated melanoma and their families, this is a tormenting period. Real advances are being made but they remain short of a cure; and they are also hideously expensive. Vemurafenib can extend the life of patient with metastatic melanoma by about a year, if it is one of the 60+% of tumours that has a mutation in the gene encoding the serine–threonine protein kinase B-RAF (BRAF). But the cost of a year’s vemurafenib is $113,000. And even if combination chemotherapy using this drug was developed which extended life beyond a year, there would be a high risk of developing other skin tumours. This phase 2 trial, paid for by Hoffmann-La Roche with company involvement at every stage, illustrates so much that is right and wrong with the current process of targeted drug development in cancer. If survival in advanced cancer is ever going to move beyond the prerogative of the wealthy, we need a whole new model of collaborative, global, not-for-profit cancer therapy research.

723   There is something deeply irritating about the names of skin conditions, which mix up Latin and Greek and seldom tell you anything useful. Lichen planus, for example. Moreover, we haven’t a clue what causes most skin diseases, and the treatment tends to be with local corticosteroids in the first instance, and oral corticosteroids if desperate. Lichen planus, for example. However, learned reviews of skin disease do tend to have elaborate accounts of molecular mechanisms and lots of sharp and lurid illustrations. Lichen planus for example; as reviewed in this article.

Lancet  25 Feb 2012  Vol 379
713    The Lancet, you may have noticed, is a seriously weird journal. One of the things it likes to do is publish the results of cutting-edge human experiments before they have any clear outcomes. Two subjects – one nearly blind with Stargardt’s macular dystrophy and the other nearly blind from age-related macular degeneration – underwent subretinal transplantation of retinal pigment epithelium cells derived from human embryonic stem cells. Four months later, not much happened. A great breakthrough, the editorial announces.

721    A few minutes after the Big Bang, when the Universe had cooled to two trillion degrees C, the first protons and neutrons formed out of the gluon-quark plasma and formed the nuclei of hydrogen and helium, together with tiny numbers of lithium nuclei. Wind on 360 000 years, when the Universe had cooled sufficiently for electrons to form stable orbits, and lithium as we know it came about. A certain amount has since been made – or recycled – by stellar nucleosynthesis. So what happens if you put lithium into people? This meta-analysis of 385 studies shows that it can be an effective mood stabiliser but carries the risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The risk of renal failure is very small but the risk of hyperparathyroidism is 10% and of the rate of hypothyroidism is increased more than fivefold. The authors recommend that TSH and calcium should be checked before starting lithium therapy and annually thereafter. They also cast doubt on the need for 3-monthly monitoring of serum levels. “Because few patients spontaneously develop toxic effects without a precipitating illness, yearly monitoring plus monitoring of one-off lithium concentrations in high-risk circumstances might be more clinically relevant and cost effective.” But this means better education of patients and doctors.

BMJ  25 Feb 2012  Vol 344
So if protons are of such ancient cosmic pedigree, what happens if we put proton pump inhibitors into people? By and large, they are happy: their gastric symptoms disappear and they want to keep taking them. But as an increasing proportion of the population take them, hidden harms begin to emerge. One of these is increased risk of fracture. This analysis of data from the Nurses’ Health Study shows that regular use of PPIs is associated with a 30% increase in incident hip fracture – increasing to over 50% in women who smoke.

For the 14 years I have been writing weekly reviews, Scandinavians have been engaged in furious argument about breast cancer screening and its contribution to the rise and subsequent decline of invasive breast cancer in those hardy regions. Here a group of Norsemen from Oslo, Bergen, and Trondheim try to promote our understanding of breast cancer trends in Norway, and conclude that “Changes in incidence trends of invasive breast cancer since the early 1990s may be fully attributed to mammography screening and hormone treatment, with about similar contributions of each factor.” But in a formidable editorial from Harvard, Karin Michels points out that “the authors do not discuss artefacts that can arise in ecological data and age-period-cohort analyses when non-linearities are present.” No doubt she is right, but I’m afraid I gave up at that point.

On to the whole question of hormone replacement therapy. It’s now ten years since the Women’s Health Initiative Study published its findings and reversed our notions of HRT and cardiovascular risk. The subsequent mass cessation of HRT caused endless hot flushes in doctors and women alike; but has the dust now settled sufficiently for us to take a balanced view of the immediate benefits versus the longer-term risks? Perhaps: and the verdict of this review is that HRT taken for five years at the onset of menopause is reasonably safe. It also confirms my feeling that we know too little about the risk/benefit ratio of hormone combinations other than the conjugated equine oestrogen/medoxyprogesterone acetate combination used in the WHI study.

Ann Intern Med  21 Feb 2012  Vol 156
I can’t think of many studies from British primary care that have appeared in the Annals, and this one receives a rave review in the editorial: “That this study was done at all speaks to the better support for high-quality research in primary care in the United Kingdom; finding support for a study like this would be extraordinarily difficult in the United States.” It’s not that easy in the UK either, and the praise is deserved: a 4-university collaborative did a cluster-randomized trial of cardiovascular family history taking by patient-completed questionnaire. It had a 98% uptake and showed that this is useful and practicable and resulted in a 4.5% increase in patients categorized as high risk.

Plant of the Week: Prunus cerasifera “Pisardii Nigra”

The earth is beginning to stir and buds are swelling imperceptibly on shrubs and trees. Among the first to open – maybe even as I write, in the gentler regions of England – will be those of this flowering cherry. It was an Edwardian favourite and is often abundant in the suburbs of that era, usually as a thirty-foot tree with an untidy trunk and dark purple leaves throughout the season. I would not recommend it for small gardens where every subject has to earn its place throughout the year, but it is a lovely sight in flower for a couple of weeks at the very end of winter.

There are plenty of these trees in the town where I used to practice, and I would look forward to their abundant pink blossom as I drove on my rounds. Wonderful when underplanted with snowdrops, or better still with scillas or blue chionodoxas. To make the tree less gloomy later in the season, train a vigorous white clematis into it – montana “Wilsonii” for May, or viticella Alba for August.

JAMA  15 Feb 2012  Vol 306
669    This week’s star Viewpoint piece is about The Unintended Consequences of Conflict of Interest Disclosure. It seems to me that twenty-first century medicine operates on roughly the same principle as the court of the Grand Vizier of the Ottoman Empire – prestige is judged by the number of bribes you are offered. Far from being a source of shame and reluctance to publish, these are routinely flaunted at the end of most interventional trials in the leading medical journals. I once counted 63 for a single individual; and perhaps he would argue that once you enter double figures, they begin to cancel each other out. How did we reach a state where the default setting of our medical culture is conspicuous corruption? As the authors here point out, this cannot go on: “Conflicts of interest, including fee-for-service arrangements, are at the heart of the astronomical increases in healthcare costs in the United States, and transparency is no substitute for more substantive reform.” And just as the US health system thinks of ways to get out of this hole, our British political masters are determined to push us into it.

674    One way in which JAMA lags behind other journals is in flagging up the role of the funder in interventional trials. It would have helped if we were told right at the beginning that Abbott paid for this study of paracalcitol in patients with an estimated glomerular filtration rate of less than 60 and echographic evidence of left ventricular hypertrophy. The title of the paper tells you little about the contents and the whole study (PRIMO) is a wonderful exercise in futility. It is completely free of clinical outcomes – a closed loop of nearly meaningless surrogate end-points relating to cardiac and renal function: and even on this basis it was a dud. Why on earth did JAMA think this worth publishing?

685    It took 60 centres in 11 countries to recruit 227 subjects for that PRIMO trial of paracalcitol (“Zemplar,” Abbott). This is not at all unusual in trials run by pharmaceutical companies on products still under patent, when the prize might be a large extension of indication. For good old amoxicillin this scarcely applies, and so for this placebo-controlled trial in acute rhinosinusitis, ten community clinics in St Louis proved perfectly sufficient to garner 166 subjects, and to prove that this particular antibiotic provides no symptomatic benefit at 3 days. There was some benefit at 7 days into the ten-day course given. This is not particularly new news, but the proximity of these two trials offers a nice demonstration of the marked difference between a pharma-funded study aimed at increasing market penetration, and a publicly-funded trial aiming to inform clinical practice. Tens of millions of dollars versus tens of thousands – and all ultimately from the pockets of the public.

713   There have been lots of recent studies linking short term air pollution and myocardial infarction and this systematic review and meta-analysis usefully combines the results of 34 of them. Small but statistically significant increases in MI can be traced to atmospheric pollution with carbon monoxide, nitrogen dioxide, sulphur dioxide and particulate matter. Another small item on the list of reasons why we need to end our dependence on carbon-based fuels.

NEJM  16 Feb 2012  Vol 366
591   Old- fashioned British general practice used to involve occasional bouts of physical exertion, such as wrestling with a patient in status epilepticus in order to give intravenous diazepam. I thought that this unique form of physical combat with an unconscious opponent had died out, but evidently it remains popular in America. This trial in older American children and adults in the pre-hospital setting shows that intramuscular midazolam given by paramedics is at least as effective as intravenous lorazepam. Worth knowing in all healthcare settings, as an alternative to the rectal, buccal, and intranasal routes.

601   It’s a familiar pattern: a pharma company (Sanofi in this case) pays for a trial based in 395 centres across 47 countries, in order to study the effect of its new drug semuloparin on the outcomes of 3172 patients receiving chemotherapy for solid tumours. The duration of the trial is 3.5 months and the end-points are venous thromboembolism, bleeding, and overall survival: the comparator is not a different low molecular heparin, but placebo. Sanofi writes up the study, with the bottom-line conclusion: “Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding.” Result: semuloparin continues to be used in most of the 395 centres and Sanofi is free to buy shed-loads of reprints from the NEJM in order to encourage clinicians to believe that their product is the one best proven to prevent VTE in chemo patients. The NEJM is free to sell these reprints without disclosing this to anyone (for “commercial reasons”), but can salve its conscience by printing an editorial criticizing the study for undue commercial bias. Both parties are winners, and cancer patients can now be treated on the basis of 3.5 months’ worth of outcome data, most of which will not even be in the public domain. This is nothing exceptional – it is the standard model of evidence-based medicine in 2012.

619   I’ve come across surgeons who were daunted at the size of their patients, but I didn’t realize that genomic scientists could be similarly affected, until I read here that “TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size.” I like the idea of thousands of gene gnomes swarming to tie down the Titin gene, like the famous illustration in Gulliver’s Travels. And this could turn out to be genuinely useful: “TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases.” Anything that brings some order and understanding into this perplexing group of disorders must be welcome, even if it takes decades to translate into therapy.

Lancet  18 Feb 2012  Vol 379
617   In the world of competitive science, it has been said that there are no prizes for coming second. It is high time we got rid of this way of thinking, especially in the clinical sciences, where collaboration needs to become the core value, where everybody should share data and where nobody should value precedence for its own sake. So let’s give a big cheer for this study of the new group B meningococcal vaccine, 4CMenB, which proves that it is immunogenic – just like last week’s study in JAMA.

633    If I’m sounding tetchy about pharma-funded trials this week, that’s because I particularly hate the kind that threaten enormous costs to health systems for tiny marginal benefits – especially where they play on our wish to do our best for patients with cancer. The logic for this GlaxoSmithKline trial is given thus: “The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy.” A hypothesis worth testing, though at current US prices, trastuzumab can cost $6K per month and lapatinib an extra $2.9K: fine while GSK are paying, and if there are robust benefits. The end-point measured, however, was purely histological – so-called pathological complete response meaning absence of invasive tumour in the breast or lymph nodes in surgery conducted after 18 weeks of treatment (with paclitaxel added for the last 12 weeks). The conclusion, written without help from GSK this time, is suitably modest: “Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting.” And if it is – which can only be determined by long-term follow up for all-cause mortality – how shall we make it affordable?

648    A very nice seminar on atrial fibrillation by Greg Lip and colleagues provides an excellent map of what has become quite a complex subject. Generalists as well as cardiologists will learn a lot from this painstaking account of the latest evidence on the treatment of a highly prevalent condition which most of us encounter at least once a day. As we gain more knowledge, treatment is becoming more patient-focussed, and more may sometimes mean less: “Lenient or strict rate control strategies might not provide great differences in outcomes, whereas the availability of non-pharmacological approaches has allowed additional possibilities for the management of atrial fibrillation in patients who are unsuitable or intolerant of pharmacological therapy.”

662    Fans of Sherlock Holmes will remember the passage in The Dying Detective where Holmes fakes delirium and attacks his dear friend Watson for being an ignorant general practitioner: “What do you know of the Tapanuli fever? Or the Black Formosa Corruption?” he rants. Modern GPs wishing to escape the opprobrium of Benedict Cumberbatch would therefore do well to read Chikungunya: a re-emerging virus.
“Ah, Watson, what are the vectors of this infection?”
“Species of the mosquito Aedes, I believe, Holmes.”
“Very good. I observe that you have been reading The Lancet, Watson. And which is the particular mosquito that may have caused the death in London of the man who lies on the carpet before us?”
“Aedes albopictus in all likelihood, Holmes. They say it may be carrying Chikungunya virus to temperate regions.”
“Watson, you excel yourself!  We must away to Baker Street for breakfast. I believe that Mrs Hudson has obtained some particularly fine kippers.”

BMJ  18 Feb 2012  Vol 344
Why are newspapers so bad at reporting the results of medical research articles? We are all very happy to blame the innate stupidity of reporters, their bias towards pharma, their bias against pharma, the dreadful state of scientific education in the UK, Rupert Murdoch, homeopaths, in fact anything other than ourselves; but might some of the fault actually lie with the poor quality of press releases from medical journals? Lisa Schwartz and Steven Woloshin have been examining these issues for many years, and one of their earliest papers was a lucid explanation of the difference between odds ratios and hazard ratios following widespread misreporting of a race-sensitive paper in the NEJM. As most doctors still struggle with this, I attach it here. Small wonder that reporters also struggle when we give them too little guidance – and here is a retrospective study which proves that bad press releases lead to bad newspaper articles.

Just because the BMJ hosts these remarks on its website does not stop me being beastly when the occasion demands. But this week (at the risk of sounding like a creep) I will say that the BMJ leads all the medical journals in providing debate and information about topical issues in medicine. This week it covers obesity treatments, commitment contracts, and new recreational drugs. Let’s take these in turn. Geoff Watts runs through obesity treatments present and future with a light touch. We have no effective drugs and we don’t really know how surgery works. But it does – and that’s a dilemma when most of the population is drifting towards overweight and obesity and the knife or the gastric band can scarcely be a general solution. Slimming clubs may have been the first to offer commitment contracts – money laid down against fulfilment of a health objective. The pros and cons are weighed up with no firm conclusion. As for new recreational drugs, you could scarcely wish for a better account of their effects and the treatment of their medical consequences. This is a must-keep article if your clientele includes the young and experimental.

Arch Intern Med  13 Feb 2012  Vol 172
209   Last year, Peter Rothwell and colleagues published a celebrated meta-analysis based on individual patient data from randomized controlled trials which showed that daily low-dose aspirin reduces total cancer mortality. This meta-analysis used summary patient data from a somewhat different set of trials and concludes: “Despite important reductions in nonfatal MI, aspirin prophylaxis in people without prior CVD does not lead to reductions in either cardiovascular death or cancer mortality. Because the benefits are further offset by clinically important bleeding events, routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis.” I wish I could take you through the merits and faults of each analysis, but I am afraid you will have to do this for yourselves. The Invited Commentary by Samia Mora provides no help in resolving the clash of conclusions about cancer mortality.

219   Back to the issue of air pollution. The JAMA meta-analysis of particulate pollution showed an increased risk in the acute situation of less than 1% for MI, but a long-term study of cognitive decline in women in relation to particulate exposure indicates a stronger effect. Live in the country, and avoid tractors.

229    The same applies if you want to avoid acute ischaemic stroke. Even “safe” levels of particulate air pollution increase your risk. Move to Vermont.

Plant of the Week: Iris reticulata

It’s hard to gain inspiration to write about plants in New England in February, but when I resorted to giving you a Hardy poem instead a couple of weeks ago, at least it climaxed with an iris. And you may well be able to enjoy the odd iris in flower during February in England, if you have planted the bulbs of the Near Eastern species reticulata. I’ve done this from time to time in the drier, more Mediterranean spots of our garden, but they have never thrived. It’s certainly a lovely thing to see their flowers – I like the light blues best – unfolding fragrantly amongst the mire and frost of an English winter; but they do have a poor, shivery look about them, and I cannot blame them for giving up.

JAMA  8 Feb 2012  Vol 307
565   There are signs that JAMA is gradually improving under its new editor, although moving its perspective pieces to the beginning of the journal doesn’t really count as progress. The BMJ has also tinkered with its order of contents, almost as if to hide the fact that they are improving at the same time. And it will certainly take a lot more than swapping chairs around to improve the Lancet. Anyway, here is a Viewpoint piece that is well worth reading if you are interested in screening and shared decision-making with patients. In a clear and well-structured piece, the authors trace the gradual path of disillusionment from the “spotting cancer early is always good” mindset to “there are harms and costs” attitudes of the present. They point out that dumping these issues on to individual clinicians to share with patients is a dubious strategy (not least in health systems where patients are called for screening independently of their normal healthcare provision). “Expert groups may dispute the ‘facts’; the science can be difficult for physicians to communicate and for patients to understand; some patients demure [sic] and want the physician to decide; physicians may lack the time, reimbursement, or motivation to engage in long discussions; and social attitudes and medicolegal pressures may influence the decision.” I particularly like their concluding sentences: “However, society’s first concern should be to confirm that screening is a net good for public health. This requires harms to be considered independently of costs. Until the reality of harms becomes more palpable to clinicians and the public, concerns about the safety of screened populations will continue to be mistaken for frugality.”

567   The next Viewpoint piece also raises an important issue in shared decision-making with patients. When we mention the potential harms of the treatment we propose – as we often must – can this interfere with its effectiveness? Again I would recommend everyone to read this article on Nocebo Effects, Patient-Clinician Communication, and Therapeutic Outcomes. This is not as coherent a piece as the previous one, but it’s good to see this discussion coming out into the open. So much simplistic talk about shared decision making ignores the extraordinary power of clinicians to instill fear and hope in their patients by the words they use and the attitudes they convey. We need to be realistic and indeed scientific about this. We have a duty to be honest, but we also have a professional and ethical duty to understand the effect we have on people in situations where they are vulnerable and we have the power to help them or harm them.

573   This study of a new polyvalent vaccine against serotype B meningococcus may mark a great moment in medical history – final victory over a horrible killer and maimer of mostly young people. The science behind it is certainly awesome: it deploys a fusion protein made up of various newly discovered antigens from different strains of type B meningococci. In this European trial the 4CMenB vaccine proves safe and moderately antigenic in infants, but how the antibody responses relate to protection from invasive disease remains to be seen. We now seem to be within sight of vaccination to neutralize the full range of pathogenic meningococci. Rejoice!

583    Bacteriologists and public health physicians in the UK try to dissuade us from using ciprofloxacin as first-line treatment for uncomplicated cystitis in young women, but in the USA the battle is already half-lost and urinary pathogens are increasingly showing resistance to fluoroquinolone antibiotics. This study examines an alternative – a third-generation cephalosporin called cefpodoxime, which seems to have been around for long enough to be available as a generic (in the UK, used by vets more than doctors). And it works: 100mg of the proxetil ester daily for 3 days works as well for simple UTI as 250mg b.d. of cipro. Possibly worth knowing.

598    Now let us praise another vaccine, this time against rotavirus. We know that this works, and saves many young lives in the developing world and hospital admissions in the USA, where it is now routinely given. What we weren’t quite sure of was whether there would an increase in intussusception following vaccination with the new pentavalent vaccine, such as caused the withdrawal of the previous trivalent vaccine. This cohort study rules that out: there was no increase in intussusception after nearly 800 000 shots given to American babies and toddlers.

NEJM  9 Feb 2012  Vol 366
489    The New England Journal alone has shown no urge to shift its contents around in the 14 years I have been reviewing it. I don’t often mention the opening Perspective pieces, but they are usually interesting and sometimes outstanding. This week you can read about the threat of untreatable gonorrhea, Medicaid battles in the Supreme Court (“All Heat, No Light” – I didn’t read further), and Preparing for Precision Medicine. The piece is co-signed by no less than Lord Darzi, once Czar Omnipotent of our humble health system, since he alone knew how to improve it. Here he sets forth a vision of medicine so perfectly guided by improved diagnostics and genomics that every intervention will achieve complete success with no harms worth speaking of. Together, we can do it! All that it will take is a little time and endless wealth. Replacing the human race would also be a good step, because as Kant said, “Out of the crooked timber of humanity, no straight thing was ever made.”

493    Neonatal screening for hypothyroidism has relegated the word ‘cretin’ to an archaic term of abuse, but an association persists between high levels of thyrotropin (TSH) in pregnancy with impaired cognitive development in children. This largely British trial looked at the effect of screening for high TSH and low free T4 at less than 16 weeks’ gestation, and giving levothyroxine at a starting dose of 150 mcg to half of the mothers with evidence of hypothyroidism and matched placebo to the other half. The (questionable) end-point was IQ in the offspring at the age of 3. There was no difference between the groups.

511    As a coffee-drinker with little interest in alternative therapies, I was under the impression for several years that tai chi was some kind of herbal tea, but apparently it is another of those things where you put your legs apart and wave your arms about, often to the accompaniment of an out-of-tune bamboo flute. Here it was compared with resistance training or stretching exercises for mild-to-moderate Parkinson’s disease. Tai chi was better than either at improving balance and reducing falls. Perhaps in Western cultural settings, it should next be compared with slow disco dancing. Like bamboo flute music, this has also been shown to foster supportive relationships, particularly amongst those trying to escape.

520    Another week, another therapy which prolongs progression-free survival in advanced breast cancer. This time it is everolimus, a derivative of what used to be called rapamycin and is now called sirolimus; and the subgroup of patients in this trial (BOLERO-2) are those with hormone receptor positive cancer who are taking exemestane. The Abstract gives two figures for the primary end-point, indicating a benefit of either 4 months or 6.5 months according to who judged “progression-free” survival. The end-point that really matters, which is overall survival, is not yet “mature,” according to the investigators: so far the absolute difference between groups is less than 2%, with far more adverse effects in the everolimus group. I think the sentences you need to read here are “In summary, we report a phase 3 trial in patients with HR-positive advanced breast cancer showing that the addition of everolimus to endocrine therapy results in an improved clinical outcome.” Note the singular use of “outcome” – these patients have 8 times the rate of stomatitis, 4 times the rate of anaemia and fatigue and ran a risk of pneumonitis which was absent with exemestane alone. The second sentence you need to read is: “Supported by Novartis, including funding for medical editorial assistance with the manuscript.”

Lancet  11 Feb 2012  Vol 379
521    This analysis of birth outcomes following assisted conception looks at 124,128 cycles of IVF that resulted in 33,514 live births, and the results are intriguing: women aged over 40 have the best outcomes. This seems counter-intuitive, and if this is a subject that interests you, you definitely need to get hold of this paper and pore over the figures. Here the bottom line will have to suffice: “Transfer of three or more embryos at any age should be avoided. The decision to transfer one or two embryos should be based on prognostic indicators, such as age.”

547   Many years ago, I put off a 3 a.m. visit to a 3-day old baby who was sleepy and reluctant to feed. Two days later he was dead from fulminating group B streptococcal disease. Hardly a day has gone by since when I have not thought of that mistake which may have cost a baby’s life, and which could and perhaps should have ended my medical career. Most general practitioners in the UK will never encounter this disease, especially in neonates, since antibiotic prophylaxis before birth is now the rule. But those who do have one chance to get it right: so any child with a hint of sepsis in the first three months of life must go straight to the paediatricians. This systematic review tries to determine the incidence of disease due to Streptococcus agalactiae in this age group, from wherever there are data: it is probably around 0.53 per 1,000 live births. The investigators add the rider that “A conjugate vaccine incorporating five serotypes (Ia, Ib, II, III, V) could prevent most global group B streptococcal disease.” I hope so.

BMJ  11 Sep 2012  Vol 344
Antibiotic prescribing in British primary care is the subject of endless debate and investigation, much of which I have found quite unpersuasive. Here is a notable exception: a real-life cluster-randomized trial of an educational intervention which really worked, albeit modestly. It is called STAR, which stands for Stemming the Tide of Antibiotic Resistance. In fact past interventions which have reduced antibiotic prescribing in primary care have shown little effect on antibiotic resistance, and it is not even a secondary end-point in this trial. Introducing the STAR programme in Welsh practices resulted in a 4.2% reduction in antibiotic dispensing. This is discussed in an outstandingly useful editorial by James McCormack and Michael Allan, which should be discussed in every training practice in the UK – and elsewhere. I particularly like the last paragraph, advising that patients should stop their antibiotics as soon as they feel better, and also that they should be told what to do if they don’t.

In my recent experience of general practice (increasingly geriatric on both sides), about half of gout is brought on by diuretics. So it’s no surprise that this trawl through the UK GP Research Database to find associations between blood pressure lowering drugs and gout points the finger most clearly at thiazides. What is slightly less expected is that beta-blockers increase the risk of gout by around a half and ACE inhibitors blockers and angiotensin II blockers increase it by about a quarter. Except for losartan, which decreases gout risk by about 20%, as do calcium channel blockers.

Surgery is like violin-playing: most people can learn how to scratch out a tune; many can learn enough to play in a band; a few learn to sound nice all the time; and a tiny handful become great musicians. Most of the great ones, like Heifetz and Milstein, did a lot of practice every day; others like Kreisler and Busch did not, and you can tell the difference technically, though they were arguably greater musicians. We all also know there are great surgeons, good surgeons, and bad surgeons: also perfectly hopeless non-surgeons, such as ourselves, who are reduced to joking about the rest. And we know perfectly well – by analogy and instinct – that this is not just a matter of case-load and experience. All learning curves do not eventually rise to the same line. This study of French thyroid surgeons does not tackle this problem of individual variation head-on, but instead related rates of damage to the parathyroids and the recurrent laryngeal nerve with number of years in post. The middle years see fewest mistakes. “Optimum individual performance in thyroid surgery cannot be passively achieved or maintained by accumulating experience. Factors contributing to poor performance in very experienced surgeons should be explored further.” Mais non: c’est la vie, mon ami. Laissez tranquilles les pauvres vieillards. Add Gallic shrug and outstretched hands.

The generally high standard and practical focus of the BMJ’s Clinical Review series is well exemplified in this week’s offering on Raynaud’s Phenomenon. It’s great to see a team of young trainee doctors coming up with a product of such quality.

Ann Intern Med  7 Feb 2012  Vol 156
173   Rooting about in the library of the Robert Wood Johnson Scholars at Yale, I was surprised to come across a copy of Epidemiology in Country Practice (1937) by William Pickles. This is the founding text of British academic general practice, though it comes from a world that has now disappeared, where a pair of doctors watched day and night over a whole Yorkshire dale. In John Pemberton’s Will Pickles of Wensleydale (1970), you can read how Pickles and his taciturn Scottish partner kept track of every case of infectious disease in their rural domain, cut off from the outside world but for a railway line to the end of the valley. When influenza struck, Pickles and his wife plotted a great chart of its progress on their kitchen wall: he had his wife drive him to the village school (he hated driving himself) and ordered that classes be suspended immediately. Alas, too late: a teacher had already spread the contagion, which moved inexorably up the dale. Most of the schoolchildren went down with it: I can’t remember how many dalesmen died. Now let’s switch to Canada, some 80 years later. An epidemic of H1N1 flu strikes Alberta, and schools are closed. Infection rates in children drop quickly. Then schools are reopened; and infection rates show a second peak. Somewhere from a moorland grave, I can hear Pickles muttering, “I bloody told you so.”

Violinist of the Week: Fritz Kreisler (1875-1962)

Many doctors are excellent violinists, but there is only one doctor amongst the greatest. As a teenager, Kreisler showed outstanding ability as a violinist and toured Europe and even America, but when he failed to get a place in the Vienna Philharmonic Orchestra, he decided to train as a doctor. He qualified, and sought career advice from one of the faculty. “Well, my boy, you can progress and become a third rate doctor, or go back and carry on being a great violinist,” he was told. Sound advice.

Kreisler was a complete natural, and his mode of playing was unique. He introduced the practice of almost continuous vibrato to his playing, which had a magical tonal and expressive power in his own hands. Unfortunately it had a generally disastrous effect on most twentieth century violinists. Because he never strove to keep up his technique (saying that “practice is just a bad habit”), his playing deteriorated with age. To get a full idea of his musicianship and mastery, listen to his recordings of the Beethoven and Brahms concertos with Blech and the Berlin Philharmonic from the earliest years of electrical recording, together with the Bach G minor Adagio (which served as a fill-up side on the 78s). To understand why nobody could resist his charm, go for the many recordings he made of his own salon pieces and imitation Baroque movements, prior to 1930. Magical, inimitable.

• http://www.youtube.com/watch?v=tA2V2JHczLE
• http://www.youtube.com/watch?v=u1BQR5ctQjU&feature=related
• http://www.youtube.com/watch?v=6un_YIawX-E

JAMA  1 Feb 2012  Vol 307
467    We of a physicianly disposition may not like to admit it, but throughout history surgeons have been well ahead of physicians at looking critically at their outcomes. For example, rates of re-operation have appeared in case series reports for well over a hundred years, so this paper on re-excision in breast-conserving cancer surgery is less innovative than it might seem, except that it goes further and looks at variability between centres and surgeons.

And actually that is nothing new either – James Simpson and Florence Nightingale were doing it in the 1860s. I’m not sure we have got all that much further in understanding this wild variation: in this survey of 4 US centres it isn’t associated with caseload at all, and isn’t even all that much to do with completeness of excision. For example, reoperation rates on patients with negative margins varied from 0% to 70% (?!) among individual surgeons, and from 1.7% to 20.9% among institutions. What is going on?

483   Shock horror: Americans are not getting fatter. We can no longer console ourselves that however bad the obesity epidemic may be in the UK, it will always be worse in the USA. Mind you, we are quite a way behind; and Americans still cherish their obesogenic environment by never serving portions that are less than twice the amount required. It’s just that nowadays in middle class circles it tends to contain a lot of unidentifiable greenery and some grated carrot. A plateau has been reached at every age group in the US, according to the latest figures from NHANHES (National Health and Nutrition Examination Survey). The 2010 obesity level was 17% overall in children and adolescents, and 36% in adults, with higher levels in black and Mexican Americans. The awful fact is that for those already obese, this is virtually irreversible by any non-surgical intervention, individual or societal.

NEJM  2 Feb 2012  Vol 366

399    Hodgkin’s lymphoma in its earlier stages became a curable cancer several decades ago, through a combination of combined chemotherapy and radiotherapy. Now we are witnessing a gradual finessing of treatment aimed at minimising the harms of curative therapy: a noble effort, where success is measured in small differences in outcome at 12 years’ follow-up. This trial was initiated in 1994 and proves by the narrowest of statistical margins that using modern staging and chemotherapy, stage IA and IIA non-bulky Hodgkin’s lymphoma survival is better if you omit the radiotherapy. Great news for people with early Hodgkin’s and a great example of patient research, in both senses of the word.

409   And now to two trials on fibroids. I don’t know why that should seem vaguely odd in the NEJM, but the editorial seems to feel the need to apologize (Uterine Fibroids and Evidence-Based Medicine — Not an Oxymoron, p.471). I suppose the point is that although there are plenty of evidence-based treatments for fibroids, most women still end up with a hysterectomy. These trials looked at the effect of ulipristal acetate, an orally available progesterone receptor modulator, in women waiting for fibroid surgery; in the second trial ulipristal was pitted against leuprolide, a GnRH agonist already in use for shrinking fibroids prior to surgery. Ulipristal certainly shrinks fibroids and may have fewer side-effects than leuprolide:  “Both the 5-mg and 10-mg daily doses of ulipristal acetate were noninferior to once-monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes.” I recently caused hot flashes in Neville Goodman by using the term “non-inferior,” for which there is unfortunately no technically suitable alternative in the English language. Alas, Nev, the medical world has few places left for us ageing pedants and purists. It is heartening to see Jeff Aronson’s learned letter on the word “surrogate” in this week’s BMJ; but the reprinted JAMA piece on Fossil Medical Words (1912) is full of the most beastly howlers in Greek spelling. The rot may have set in 100 years ago – in America, of course.

Lancet  4 Feb 2012  Vol 379
Fuddy-duddies wishing to enjoy hot flashes of rage at bad English generally go to two places in the medical literature: the poetry section in JAMA and Offline by Richard Horton. The JAMA offering this week is beyond human endurance, while Offline reverts to being merely dotty, with the odd bum note that most readers would hardly notice, such as “his stunning musical career took off—aged 8.” While praising Donizetti, Horton begins his section by disparaging a plate of brains he saw in an Italian restaurant. This is most unfair. Brains are a great delicacy and the Italian way of preparing them in batter is delicious. And those over 60 need hardly worry about Creutzfeldt-Jakob disease with its incubation period of around 50 years (possibly shorter if you eat squirrel brains).

413   The Bill and Melinda Gates Foundation funded this study of malaria mortality between 1980 and 2010 – all part of the noble effort that we Microsoft users put into global disease eradication (what have you trendy Apple users got to say for yourselves? Eh?). As you will have read by now, the adult death rate may be around twice what we previously thought, hovering around a million a year. Previous attempts at global malaria eradication foundered on Cold War competition to produce genocidal weaponry and land a man on the moon. Now it might be worth addressing this before sending a man to Mars.

432    Here is another massive effort: Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. The conclusion of the editorial sums it up perfectly: “The EBCTCG meta-analyses continue to show that polychemotherapy saves lives (and that it can, on average, reduce breast cancer mortality by about a third). Clearly, the actual benefit and harm of polychemotherapy will be determined by the individual future risk of relapse and coexisting comorbidities. The challenge now is not only to save more lives, but to reduce the number of women given polychemotherapy unnecessarily. It is with such hope that the results of ongoing oncomolecular trials are awaited. We look forward to the day when treatment of fewer women with a personalised approach achieves more.”

453    Even better is the editorial on this study of cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC). State-of-the-art cardiac MRI is pretty amazing at spotting coronary atheroma, and better than state-of-the-art CT (SPECT); but that is no reason to rush to adopt the new technology. Robert Bonow’s words have resonances far beyond cardiac imaging: “Enhanced diagnostic accuracy of CMR must be balanced against availability and cost-effectiveness, and there is a need for evidence of measurable improvements in patient outcomes. Diagnosis of coronary artery disease alone is not sufficient to determine the need for revascularisation. To show value, advances in imaging must be coupled with enhanced patient well-being or a reduction in unnecessary downstream testing and procedures.”

461   For your further intellectual nourishment this week The Lancet offers seminars on Lyme borreliosis, hereditary angio-oedema and low back pain. Hereditary angio-oedema is caused by C1 esterase deficiency, and if you have a patient with it the chances are that he or she will be able to tell you all you need about it (including tales of relatives who died from laryngeal involvement). About low back pain you already know as much as anyone else. This seminar on Lyme disease, however, has already come in handy as it was already on the Lancet website last July, when my wife and I hired a car and passed through Old Lyme, Connecticut, on our way to a highly recommended coastal nature reserve. This consisted of reedy marshland and woodland areas full of bracken and stagnant pools of water. After two hours we emerged covered from head to toe in insect bites which became gross and sometimes haemorrhagic, spreading out in large erythematous circles over several days. But we took no antibiotics, and after a few hot nights, rendered sleepless from itching, the spots settled. I don’t think we have Lyme disease, though thousands of Americans believe that they have the chronic form and rage incessantly at anyone who disbelieves them. If we eventually become delusional, you’ll all regret we didn’t just take some tetracycline in good time.

BMJ  4 Feb 2012  Vol 344
Three papers in this week’s BMJ examine the decline in mortality from myocardial infarction in European countries. The first is England, a part of the United Kingdom which was oddly missing from the European MONICA study in the 1980s and 1990s. This record linkage study shows an astonishing fall in standardized mortality from myocardial infarction of one half between 2002 and 2010. This is unevenly spread across England, as most things are, but in this case there is no evidence of a clear North/South divide. Nearly half of the drop is attributed to improved survival at 30 days. Most deaths from MI in England are now sudden deaths outside hospital.

In Denmark, a similar decline has occurred, but measured over 25 years rather than 8.

The investigators from Poland prefer to measure their halving of cardiac mortality from 1991: “Over half of the recent fall in mortality from coronary heart disease in Poland can be attributed to reductions in major risk factors and about one third to evidence based medical treatments,” they conclude. By means of different kinds of modelling, they attribute this to “socioeconomic transformation”, ie liberation from the yoke of socialism. Perhaps we in England should attribute ours to Tony Blair, though I would rather not.

A somewhat worrying report from five Scandinavian countries suggests that taking serotonin reuptake inhibitors during pregnancy may double the risk of persistent pulmonary hypertension in the newborn. This is billed as a population cohort study but is really a case-control study. The risk seems greatest when SRIs are taken in the last weeks of pregnancy – unfortunately just when one would least wish to discontinue them.

Plant of the Week: Rubus cockburnianus

Basking in temperatures of 5 degrees and more here in New England, we think anxiously about you left in old Britain as it snows and freezes. Often the plants that look best in such conditions are the brambles that we love to hate all the rest of the year. Covered in rime, their stems and even their leaves can take on a sort of hoary magic. Once the ice has melted, you can go back to cursing and bleeding as you struggle to extirpate them. Here in New England there are curiously few wild brambles, or even nettles, making its woods a delight to wander in (so long as you avoid poison ivy).

If you want a bramble that looks good all the year round, this one is worth trying – but only if you are prepared to give it about fifty square yards of ground, or fight a losing battle to contain it. The white stems look wonderful all winter, and there are various varieties with goodish leaves for the rest of the year. R cockburnianus is not quite as invasive as the common bramble, and when we finally decided to extirpate our bank of it, it only took about five goes and less than a pint of blood.

JAMA  25 Jan 2012  Vol 307
373   Here’s the kind of study that’s all too rare in the medical literature: an important interventional trial that is not funded by pharma. The question is whether giving a proton pump inhibitor can improve outcomes in poorly controlled childhood asthma: a reasonable hypothesis to test, since a high proportion of such children have been shown to have asymptomatic acid reflux. This double-blind RCT recruited 306 children from 19 US centres, and shows that daily lansoprazole has no benefit and that it may have important harms. The active drug group had more respiratory infections and markedly more fractures (6 vs 1): not to the point of statistical significance, but definitely to the point of warranting an urgent database study of fracture incidence in children taking regular PPIs.

NEJM  26 Jan 2012  Vol 366
299     The history of breast cancer is strewn with the tragedies of millions of women made to suffer through wishful thinking. William Halsted introduced ever-more mutilating radical mastectomy in the 1890s, which remained popular in the USA for nearly a century; then came screening mammography, with its spectacular rates of overdiagnosis; and now a series of phenomenally expensive and marginally effective monoclonal antibodies against molecular targets, as illustrated by bevacizumab. Last November, the FDA revoked its approval for this vascular growth factor A inhibitor in metastatic breast cancer, but meanwhile two large trials of bevacizumab in early breast cancer had been completed. Both of these use a surrogate end-point called pathological complete response, meaning absence of invasive and intraductal disease in the breast and the axillary lymph nodes. Used in combination with neoadjuvant chemotherapy, bevacizumab has a barely discernible effect on this debatable end-point: an absolute increase in response of less than 5% in the first trial, and 2.1% in the second. In both trials, a subgroup could be found where the response rate was slightly larger, but the results seem at odds with each other: triple-negative tumours in the first, and oestrogen receptor positive tumours in the second. No matter: the cost of bevacizumab in these trials was about $50 000 per patient treated, and it will have to do a great deal better than this. Being shown to save a life would be a start.

321   But of course, nothing ever saves a life. If we don’t want to die of cancer, we might as well die of cardiovascular disease. Perhaps sooner rather than later, since “happiness (is) but the occasional episode in a general drama of pain.” (Thomas Hardy, final sentence of The Mayor of Casterbridge, 1886). Tush, I must stop reading Hardy and take some citalopram. Here is a classic paper which describes the lifetime risks of cardiovascular disease: though the very fact of its being a printed article places absurd limits on its usefulness. A meta-analysis like this, covering more than a quarter of a million people from the age of 45 till death, needs a whole website with full databases and several banks of Powerpoint slides. Traditional publishing is rubbish when it comes to a topic like this: and you don’t even get open access to these printed titbits. Suffice to say that wherever you live and whatever your ancestry, your CV risk is a simple function of four factors: blood pressure, smoking, cholesterol, and diabetes. These are all continuous variables, and we are looking at 18 cohorts studies involving 257,384 individuals. And here is an 8-page article: what a way to carry on in the year 2012!

339    Like most British general practitioners, I have never prescribed fingolimod for multiple sclerosis. In fact I had only the faintest notion of the existence of thingummybob, and only read this review article because it seemed the sort of name it would be easy to make jokes about. Well, here is a little joke for you. You are a GP who has decided (or rather been forced) to take part in your local commissioning group, aided by five tiers of NHS management (so as to save costs). Your patient Toni is a teacher with two school-age children who developed MS three years ago and has been unable to work for one year. She experienced severe adverse effects with interferon-alpha and during her latest flare-up she became incontinent and has had walking difficulties ever since. She is becoming unable to care for her children. Her neurologist has suggested treatment with oral fingolimod, subject to approval by your commissioning consortium. This will cost £15K per annum, and the consortium has been instructed to make group savings of £2M to cover last year’s deficit. You read this review article which provides a useful overview of all MS treatments and indicates that fingolimod could reduce her relapse rate considerably but has no proven effect on progression of disability. Its long-term safety is unknown and individual response is not predictable. How do you share the decision about what to do next with your patient? And your consortium? This of course is what you will end up doing all the time if the 50 signatories to the Daily Telegraph letter have their way. (And now, finally, the joke [sorry]: Q: what is a signa-tory? A: someone who signs letters in the Tory press.)

Lancet  28 Jan 2012  Vol 379
315    Following gastric cancer surgery which is intended to be curative, adjuvant chemotherapy is generally agreed to improve survival, but this has not been demonstrated specifically for D2 gastrectomy followed by capecitabine and oxaliplatin. OK, I know you aren’t interested in the details of chemo for specific cancers, but this trial raises again the issues of what end-points really matter. To a fundamentalist like me, the principal issues are all-cause mortality and quality of life. But most cancer triallists prefer recurrence-free survival, a composite outcome, which is easier to arrive at in terms of time to statistical significance. In this case, the chemo increases disease-free survival and the chart for overall survival is promising. The price is nausea, lack of appetite and neutropenia for the majority of patients.

322    I’ve already commented on this meta-analysis by Carl Heneghan et al of individual patient data relating to self-monitoring of anticoagulation, which has major implications for clinical practice. Come on, primary care academia: there is more low-hanging fruit like this if only you would get on and pick it.

335    I’m no great fan of screening in general, but most neonatal screening is self-evidently a good thing, because it detects rare but important metabolic defects which have a known natural history and a known treatment. If this knowledge did not exist, screening would simply be a recipe for lifelong distress and anxiety. In this paper an Austrian population study shows that neonatal screening is possible for several lysosomal storage disorders: Gaucher’s, Pompe’s, Fabry’s and Niemann-Pick types a and B. These proved to be commoner that expected, with an overall incidence of 1 per 2315 births, dominated by Fabry’s disease, an X-linked condition which has a late-onset prevalence in Austria of 1 per 4100 (the paper says incidence, but I assume this is an error). There is a moderately useful enzyme treatment which prevents cardiac and renal damage in Fabry’s disease, which is an argument for early diagnosis; on the other hand, this only applies to the classic phenotype. I think we need some very robust modelling and much thought before going in for this particular mode of whole-population screening.

361   For seminars this week, The Lancet can offer you cryoglobulinaemias, acne vulgaris, or thalassaemia. As we have already strayed far into recondite topics, let’s return to that most familiar of spots, acne. If you don’t know a lot about acne, this review will tell you everything you need to know. If you do know a lot, it will remind you that trimethoprim is a good alternative to the tetracyclines, and that no kind of oral contraceptive has been shown to clear acne better than any other.

BMJ   28 Jan 2012  Vol 344
I know I go on a lot about surrogate outcomes, but surely weight loss in obese people, especially if they have diabetes, must be a good thing? Well, no, in fact: sibutramine and diethylpropion both reduced weight – and thus glycaemia in type 2 diabetes – but resulted in more harm than benefit. Agonists of the glucagon-like peptide-1 receptor (GLP-1R) have a weight-reducing action in both diabetic and non-diabetic subjects, as this systematic review demonstrates; and they are as effective as any other non-insulin agents at lowering glycated haemoglobin. But that does not of itself make them either safe or useful. They should not have been licensed without clear evidence of long term benefit as measured by cardiovascular events and all-cause mortality.

My mother was diagnosed late with ovarian cancer, and died a year later. Do I blame her GP? Of course not. Unless discovered incidentally by imaging or laparotomy at an early stage, ovarian cancer is always diagnosed too late for a cure. In fact it is such an insidious and ill-understood disease that even in women with BRCA mutations who have undergone prophylactic removal of both ovaries, it can still present with omental secondaries and a pelvic effusion. Yes, studies show that with hindsight, women usually present with symptoms a few months before they are diagnosed – usually with a description of abdominal fullness that doctors confuse with bloating. Listen carefully to the patient – if she says her tummy feels bigger all the time, get an ultrasound scan. I suspect that is just as good as the computer algorithm for earlier diagnosis of ovarian cancer devised and validated here by the Nottingham group. But however you diagnose it, don’t expect to save any lives.

Arch Intern Med  23 Jan 2012  Vol 172
98     Ever since immediate percutaneous coronary intervention was shown to be superior to thrombolysis for high-risk ST-elevation myocardial infarction, health systems have been pouring huge resources into providing 24-hour immediate PCI facilities, but with inevitably mixed success. Outcomes researchers in the USA have come up with some pretty dire statistics for time to transfer from hospitals without PCI capacity to hospitals with, and in this editorial Rita Redberg grasps the nettle and urges a more realistic approach: “For low and intermediate risk patients, there is no mortality advantage to pPCI over thrombolytic therapy. Even for high-risk patients with STEMI, the mortality benefit of pPCI is frequently lost due to routine delays of 1-3 hours by transfer. It is time to reconsider transferring patients with STEMI for pPCI. Timely reperfusion by thrombolytics, not late pPCI via transfer, will save lives.” Discuss.

101    Popular myth tells us that exercise combats depression by producing endorphins – or is it serotonin? – and for all I know popular myth may be right. There’s no doubt that exercise has other benefits too, so it’s nice to know from this systematic review that the antidepressant effect of exercise in chronic illness is supported by evidence from a large number of trials in a large range of conditions.

144    I would like to claim that the population benefits of taking statins are not outweighed by any potential for irreversible harm, and that now they are so cheap there is no reason why anyone should be advised against taking a statin if they wish to reduce their cardiovascular risk. There is no threshold effect, after all. But now there is a nagging worry that statins may induce diabetes, confirmed here by data from the Women’s Health Initiative, which included over 150,000 postmenopausal women without diabetes at baseline. This needs a lot more investigation: there is a lot of scope in such studies for residual confounders, including confounding by indication; and we need to know more about the potential reversibility of statin-induced hyperglycaemia.

Poem of the Week: Her Apotheosis by Thomas Hardy

Having mentioned Thomas Hardy the nineteenth-century novelist at his most morose, I think I should give you a poem illustrating Thomas Hardy the great twentieth-century poet at his best – enigmatic and not all that morose:

There were years vague of measure
Needless the asking when;
No honours, praises, pleasure
Reached common maids from men

And hence no lures bewitched them,
No hand was stretched to raise,
No gracious gifts enriched them,
No voices sang their praise.

Yet an iris at that season
Amid the accustomed slight
From denseness, dull unreason,
Ringed me with living light.

I read the poem several times aloud, wondering at the sudden appearance of the iris, whether flower or eye, which breaks the rhythm and rings the woman with living light. Hardy’s motto for the poem, Secretum meum mihi, and his subtitle, Faded Woman’s Song, give little away.

And then I looked it up on Google and got this travesty instead:

There was a spell of leisure,
No record vouches when;
With honours, praises, pleasure
To womankind from men.
But no such lures bewitched me,
No hand was stretched to raise,
No gracious gifts enriched me,
No voices sang my praise.
Yet an iris at that season
Amid the accustomed slight
From denseness, dull unreason,
Ringed me with living light.

I assume this is the final version; but authors so seldom know best.

JAMA  18 Jan 2012  Vol 307
265     Cangrelor is one of a number of reversible thienopyridine platelet inhibitors competing to replace clopidogrel. This could be an enormous market, but the BRIDGE study, funded by The Medicines Company, begins with a small niche: patients who discontinue antiplatelet treatment before elective coronary artery bypass grafting. The problem that this study is alleged to address is the risk of rebound coronary events in such patients, unless some kind of platelet inhibition is maintained up to near the time of surgery (using IV cangrelor, of course); but in fact a coronary end-point appears nowhere in the trial. Instead, the primary end points are bleeding during surgery and laboratory platelet function tests. These lab tests are the weakest of surrogates, and I am unconvinced that there is a problem here that cannot be addressed in a simpler way. This study really doesn’t belong in a leading medical journal.

275    Caffeine has a very important role in special care baby units, but this study shows that there is little point giving it to the babies. Previously it seemed that caffeine given to very premature infants with breathing problems can reduce the rates of cerebral palsy and cognitive delay at 18 months; but sadly follow-up at 5 years shows that any benefit disappears with time. Caffeine is strictly for NHS staff.

294    It was a long time before orthopaedic surgeons were persuaded to take seriously the problem of venous thromboembolism following lower limb arthroplasty, but postoperative prophylaxis is now a quality marker in most hospital systems. However, this analysis of 44 844 patients from 47 studies shows that even with standard treatment, one patient in 100 gets VTE before hospital discharge following total knee replacement, and in 200 following total hip replacement. And the editorial points out that this is not the largest problem: in a Californian study, 76% of THR-associated VTE events and 47% of TKR-associated VTE events occurred after hospital discharge. These patients need a much longer period of VTE protection, amounting to 12 weeks following THR, and 6 weeks following TKR. If I was the manufacturer of a new anticoagulant like idrabiotaparinux, I would be getting my RCT organized right away.

NEJM  19 Jan 2012  Vol 366
207    I managed to finish Mukherjee’s weighty book, The Emperor of All Maladies, in time to lighten my suitcase before returning to the USA, and I liked the way it ends on an ambivalent but somewhat optimistic note about progress in cancer. As our mechanistic understanding gradually develops through genomic analysis, so we can start picking away at one pathway and then another—a speeded-up, better-focused version of what cancer therapeutics has been doing over a period of seventy years. But one story after another illustrates how effective cancer cells can be at outwitting each new kind of targeted therapy. The example here is malignant melanoma, some strains of which melt away almost completely with the BRAF inhibitor, vemurafenib. But a few months later, the metastases usually come back: and they tend to be accompanied by a troop of other skin tumours such as squamous cell carcinomas and keratoacanthomas. This is related to the presence of RAS mutations, which in a mouse model can be inhibited by a MEK inhibitor. The future of cancer therapeutics may lie in this kind of sophisticated game of tag: but is this really going to be affordable by more than a few lucky individuals?  There is another Big C we have to conquer, which is never mentioned in Mukherjee’s book—Cost.

225    A lot of the costs of a health system depend on how often you do things, and often there is little evidence to guide decision-making. This very useful study explores the question of how often it is worth measuring bone mineral density in older women. Enrolment of women (almost entirely white-skinned) aged 65 and over began in 1986 at four sites in the USA, and there were five further BMD examinations up to 2004. “Our data indicate that osteoporosis would develop in less than 10% of older, postmenopausal women during rescreening intervals of approximately 15 years for women with normal bone density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia.”

250   An outstanding review of Cognitive and Neurologic Outcomes after Coronary-Artery Bypass Surgery does much to allay fears raised by studies over the last decade which seemed to indicate that CABG carries a high risk of cognitive impairment. “It is now increasingly apparent that the incidence of both short and long-term cognitive decline after CABG has been greatly overestimated, owing to the lack of a uniform definition of what constitutes cognitive decline, the use of inappropriate statistical methods, and a lack of control groups.” Older patient undergoing CABG are at high risk of cerebrovascular disease anyway, but “although some degree of short term cognitive decline may occur days to weeks after CABG, these changes are generally minor and temporary.”

Lancet 21 Jan 2012  Vol 379
229     Critical care units are places where desperate remedies are tried out on desperately sick people. If people on ventilators are choking to death with acute respiratory distress syndrome, then the temptation arises to use intravenous beta-adrenergic agonists.  This British trial (BALTI-2) showed that this induces tachycardia, arrhythmias, and lactic acidosis (as expected), and it was stopped once mortality in the treated group significantly exceeded that in the placebo group.

236    As I go through the journals every week, it’s always a relief to alight on a good observational study: at least the authors are probably trying their best to be honest. Most adolescents who self-harm grow out of it: a nice common-sense finding from following up nearly 2,000 schoolchildren from a mean age of 15.9 months up to a mean age of 29 years in Victoria, Australia. Quite a lot of useful work can be done by picking up the phone to chase a cohort from time to time. But there are few clues as to how to pick out the ones who will become recurrent, or who will kill themselves. Keith Hawton, who has been working in this field for at least 40 years, drops no hints in his editorial.

244   Here’s a really great observational study from Sweden looking at over half a million people who were admitted to hospital with an auto-immune disorder. Their overall risk ratio for pulmonary embolism during the first year after admission was 6•38 (95% CI 6•19—6•57). But it was particularly high for certain conditions: immune thrombocytopenic purpura (10•79, 95% CI 7•98—14•28), polyarteritis nodosa (13•26, 9•33—18•29), polymyositis or dermatomyositis (16•44, 11•57—22•69), and systemic lupus erythematosus (10•23, 8•31—12•45). It might seem a bit odd to give anticoagulants for ITP, but it’s looking as if that might be a good idea. Time for yet more trials using next-generation factor Xa and thrombin inhibitors.

BMJ   21 Jan 2012  Vol 344
The National Perinatal Epidemiology Unit in Oxford is two years late in reporting its survey of Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies, during which time many smaller British hospital maternity units have been closed and replaced by stand-alone midwife led delivery units. To me, the figures given here lend no support to this policy. Up to 45% of primiparous women booked for midwife unit or home delivery ended up being transferred to hospital during labour, which I think is a shocking statistic. I quote from a Rapid Response by Margaret Treadwell: “For low risk nulliparous women without complications at the start of labour the risk of one of the serious ‘primary outcomes’ is: 22 cases out 4785 in a free standing midwifery unit, 28 cases out of 8018 in an obstetric unit. And for stillbirth; 0.4 per 1000 in a freestanding midwifery unit, 0.2 per 1000 in an obstetric unit. This is BEFORE adjustment for the increased risk profile of women choosing obstetric unit care and an acknowledgment that there may have been some data loss due to transfer. These figures do not reach statistical significance but perhaps we should pause for thought, dig a bit deeper and ask a few more questions before reconfiguring the entire country’s maternity services.” Too right we should.

How quaint that it needed the Whitehall II Prospective Study to prove that cognitive decline begins in the mid-40s. But young people should be consoled that as one gets older, one becomes more used to working in the absence of short-term memory, and better at pretending that no-one notices. By the time that one is truly convinced of one’s abiding wisdom, the chances are that Alzheimer’s has properly set in.

The standard method of diagnosing localized prostate cancer is by transrectal biopsy. As this paper cheerily notes, “TRUS-Bx can be associated with appreciable morbidity, including sepsis, pain, bleeding, and even death on rare occasions.” As part of the Prostate Testing for Cancer and Treatment (ProtecT) study, the investigators determine the acceptability of TRUS amongst 1147 British men who underwent 10-core biopsy following the detection of a raised PSA. About one man in five would have serious doubts about ever having the procedure again: testimony to true British grit on the part of the rest, I think. Naturally the degree of pain was the main determinant of reluctance, as discovered by Corporal Jones when he served under General Kitchener: “They don’t like it up ‘em, sir, they don’t like it.”

“Consider antineutrophil cytoplasmic antibody (ANCA) associated vasculitis when inflammatory disease cannot be ascribed to any other disease and inflammation progresses despite antibiotics.” Wise words, but you will have some trouble identifying these conditions in general practice, if my own experience is anything to go by. In fact, I would like to have grabbed this topic for the Easily Missed series, but here is a more extensive and learned disquisition by a team of Dutch specialists instead. Granulomatosis with polyangiitis is one form, which used to bear the name of the Nazi criminal Wegener; the other kinds are microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). These conditions used to be rapidly life-threatening and still are not altogether understood or conquered: so don’t delay referring anyone who is coughing or sneezing blood, looks ill, and has a spectacular CRP.

Ann Intern Med  17 Jan 2012  Vol 156
105    Did it ever occur to you that giving high dose vitamin D to an unselected cohort of patients with chronic obstructive pulmonary disease might prevent exacerbations? Me neither. But a group of Belgian chest doctors thought it was worth a try, and have proved that it doesn’t work. There has been a bit of a backlash against vitamin D lately, notably in a recent Lancet editorial deploring the increasing number of vitamin D assay requests in UK practice, but I remain modestly hopeful that some benefit will emerge from lengthy prospective studies. But not in COPD.

115   Obstructive sleep apnoea is generally regarded as a male prerogative: indeed it is often considered a form of deliberate moral turpitude by the wives and partners of those afflicted. But women gasp and snore and jump about in bed too, and they generally don’t do it on purpose. The penalty for this behaviour is nothing less than cardiovascular death, and the cure is continuous positive airways pressure. Here a group of Spanish investigators attempt to determine the degree to which CPAP reduces the increased risk of CV mortality in women, but their observational study is flawed and underpowered to reach a useful estimate. There is a definite trend to benefit, however.

123   Here’s another study comparing real autopsy with “virtual” autopsy using CT and MRI, this time carried out on deceased patients from German intensive care units. There were full comparisons in only 47 patients, and once again these tended to show that important cardiovascular causes, and even some cancers, were not picked up on imaging alone.

147    What happens in the UK if you send a patient to a private specialist or a tertiary centre for a second opinion? Invariably they repeat all the tests. In the USA, where patients are much freer to come and go and demand what they like, diagnostic and screening tests are a huge burden on the system, and a major factor in making health care unaffordable. Here a group of American physicians looks at the concept of cost-conscious, high-value care as an aspiration for their health system. They could learn a lot from the NHS, though I don’t suppose Newt Gingrich will be making this a central plank of his election campaign. The authors here identify 37 common clinical scenarios where a test does not reflect high-value care. If you have a bit of spare time, you could look up their list and try to think of 37 more.

Plant of the Week: Leucojum vernum

Before returning to the snow and ice of New England, we had a chance to enjoy the winter flowers of England. Our treasured rose, Grϋss an Aachen, was still trying to flower till after Christmas, and then came primroses and spring snowflakes, even before the snowdrops and aconites.

I don’t know if we have a special clone, but our variety of spring snowflake (Leucojum vernum) tends to flower very early indeed – usually at the same time as its smaller cousins, the snowdrops. These bulbs come from the woods and meadows and stream banks of central Europe, but we plonked them on a sun-baked bank of limy clay, where they have flourished ever since. Tough, therefore, and indispensable for their early presage of spring.

JAMA  11 Jan 2012  Vol 307
157    There’s a general feeling among cardiologists that low potasssium is a bad thing, but this interesting observational study of 38 689 patients with acute myocardial infarction shows that a high potassium can be even worse. On admission with AMI, potassium levels are normally distributed (figure 1): mortality in relation to potassium levels thereafter follows a  classic U-shaped distribution, bottoming out under 10% between 3.5 and 4.5 mmol/L but hitting an alarming 60+% by the time you reach the pretty modest level of 5.5 mmol/L. The strength of the association on both sides of the curve really is quite dramatic, which presumably is why JAMA is releasing the full text of this paper free online. What it means for clinical practice is not for me to guess: go instead to the learned editorial.

173    The only objection I have to people smoking marijuana is that it sometimes makes them a bit vague and boring; perhaps it can also unmask psychosis on rare occasions, and of course it usually involves inhaling tobacco smoke. This curiously hyped observational study looks at people who smoke pot on a median of 2-3 occasions per month. That’s an awfully tiny amount of tobacco, or indeed hemp. No wonder it has no discernible effect on pulmonary function over 20 years.

182    “So teach us to number our days, that we may apply our hearts to wisdom” (Ps 90;12) is the text I usually preach to when discussing prognostic indices for older people. Now that I’m an older person, I am increasingly unsure about what particular wisdom to apply my heart to. It’s a toss-up between the wisdom that it’s nearly all over for me, and it’s time to pack it all in and relax; or the wisdom that the world is a place that still needs some attention, and one should try one’s best for as long as possible. I certainly don’t want anyone telling me when they think I am going to die. If I did, I would ask them to measure my BNP, cystatin C, and copeptin, serially. This systematic review does not deal with biochemical tests, rather with a number of scoring instruments which are not disease-specific. Using these, you can decide whether people are still worth putting through various forms of cancer screening or being given preventive drug treatment such as statins. The patient really doesn’t get much of a look-in in this paper: presumably the idea is that doctor says to the patient, “Now look here old thing, everything points to the fact that you’re going to pop you clogs in the near future, so let’s not bother with any of this any longer, eh?” Personally, I’d rather the patient said this to the doctor.

NEJM  12 Jan 2012  Vol 366
109    I am nearing the end of Siddhartha Mukerjee’s exuberant history of cancer, The Emperor of Maladies (2010), where he is about to reach the story of “Herceptin” in the early 1990s. I am amazed that this drug, which should be called by its real name, trastuzumab, was around as long ago as that. Surely it should be off patent by now if that is the case? Anyway, long experience has taught us that given alongside docetaxel, trastuzumab provides very little worthwhile benefit in advanced metastatic HER-2 positive breast cancer. Pertuzumab is another monoclonal antibody which targets the HER-2 receptor, but by another mechanism, so the uzumabs act synergistically. This is shown to have marginal clinical benefit in this manufacturer-funded trial which randomized 808 women to either trastuzumab with paclitaxel, or to both drugs with paclitaxel. The latter group showed progression-free survival of a mean 18.5 months as compared with 12.4 months, which sounds impressive, but the overall mortality difference did not reach significance. In other words, the number needed to treat to affect survival was not determinable within the 400 randomized to this treatment, and any possible gain in lifespan would involve spectacular expenditure in the clinical setting – if indeed it is achievable at all. There are plenty of other similar agents in the pipeline, which the editorialist describes, apparently without irony, as “an abundance of riches.” For whom?

120    Do you have paroxysmal atrial fibrillation? You might, perhaps while you are asleep, or so asymptomatic that you know nothing about it. The ASSERT study found evidence of atrial tachycardias in 10% of a population fitted with pacemakers or implanted defibrillators over a period of 3 months. In the next two-and-a-half years, these people had nearly three times the risk of stroke and over five times the risk of developing permanent AF. Should we screen for it in this population? Should we offer them warfarin? Or rivaroxaban? Over to the triallists.

130    The Greek word for fennel is marathon, and it was on a fennel covered field that the Greeks repulsed the army of Persia – a most regrettable encounter which has retarded the progress of civilization to this day. To quote Wikipedia: “The traditional story relates that Pheidippides (530 BC–490 BC), an Athenian herald, was sent to Sparta to request help when the Persians landed at Marathon, Greece. He ran 240 km (150 mi) in two days. He then ran the 40 km (25 mi) from the battlefield near Marathon to Athens to announce the Greek victory over Persia in the Battle of Marathon (490 BC) with the word “Νενικήκαμεν” (Nenikékamen, “We have won”) and collapsed and died on the spot from exhaustion.” Serves him right: it was a very foolish thing for a forty-year old man to do. Moreover, if he was so out of breath, he did not need to use the reduplicative aorist. Male marathon runners continue to drop dead at an increasing rate (2 per 100,000), and this study identifies the chief causes as atherosclerotic coronary disease in the older runners and hypertrophic cardiomyopathy in the younger. If only the Persians had won: we might have a world free of marathons, Olympic games and unhelpful Greek medical terms like hypertrophic cardiomyopathy (or such really exotic examples as paragonimiasis).

Lancet  14 Jan 2011  Vol 379
123    Idrabiotaparinux is a word which belongs to no known human language: it is made up of “idraparinux” (perhaps inspired by the characters in Astérix, as this is a French drug) and biotin, sometimes known as vitamin H (a Greek root sneaks back in here). You will, I am afraid, have to memorise this word, because idrabiotaparinux marks a breakthrough in anticoagulation. It is a safe, effective anticoagulant which inhibits factor Xa : it has a terminal half-life of 66 days and a simple antidote in the form of avidin (an egg-derived substance). In this study, it was given by weekly subcutaneous injection, but there seems no reason why that could not be monthly. Patients with acute symptomatic pulmonary embolism were started on enoxaparin and then allocated (with complex blinding) either to idrabiotaparinux or to INR-adjusted warfarin. As usual in The Lancet, the manufacturers are allowed to sneak statistically non-significant claims for their product into the abstract: but the fact remains that idrabiotaparinux is non-inferior to warfarin in preventing VTE following PE, and probably a lot more convenient for most patients.

136    Paris became the world’s chief centre for medical education around 1800, just after the Revolution, when the city’s main hospitals were secularized and integrated into a massive teaching unit. Here students from America and all over Europe could question and examine thousands of inmates and then discover the causes of their illness in post-mortem examinations. A few patients had the temerity to survive, but the rest were invariably dissected. Now, alas, there are but few corpses on the pathologists’ slabs: the modern doctor may make fewer mistakes, but she or he can bury or burn them with greater impunity. Pathologists from Manchester and Oxford demonstrate here that scanning is no substitute for prosection – CT is better than MRI but still inadequate in a third of cases. Imaging is particularly inaccurate in determining the cause of sudden death. If we are to get at the truth, we need to become more like the post-revolutionary French. Vive la morgue!

153   I guess most of my readers have never seen measles, and this punchy review will not help them to recognize it the way we used to, as a febrile, spotty, red eyed child came coughing into the consulting room. The nearest you get is a rather ancient illustration of Koplik’s spots. Hopefully doctors in generations to come will never need to recognize the disease at all, as it does not exist outside humans and is a prime target for global eradication. At present it still kills more than 100,000 people a year and is one of the most contagious diseases of all – it can propagate even if less than 10% of the population is susceptible. Keep vaccinating.

165    Unlike measles, the great majority of chronic kidney disease is totally invisible. So invisible, in fact, that most people with it never experience anything. They are silently suffering from a form of organ failure so subtle that, left alone, they will die of something else without ever being aware of it. I skimmed this review dutifully to see if I was missing some deep reason why we should awaken our elderly patients from this blissful state of ignorance, but found none. The authors are particularly emphatic that most long-term interventional trials in “CKD” are inadequate to form the basis of a population strategy.

BMJ  14 Jan 2012  Vol 344
The Hypertension in the Very Elderly Trial (HYVET) recruited 3845 subjects over the age of 80 using a huge team of investigators from 11 countries, dominated by Bulgaria, Tunisia, and China, between 2000 and 2003. Indapamide was the main intervention used to get the systolic BP under 160mm Hg – a strange choice since there are so many other thiazide diuretics that cost practically nothing. The second-line drug was perindopril, also made by the co-sponsor of the trial, Servier. Oh well: there are no doubt plenty of people still taking these drugs in the centres chosen. And they continue to benefit, as the BMJ shows us in this paper about an open-label follow-up cohort; though I imagine the subject who was 105 at the start may no longer be among them.

An intriguing study of the UK General Practice Research Database suggests that taking bisphosphonates doubles the lifespan of joint replacements. This could be an immensely important discovery, though it clearly needs to be replicated in prospective trials. It is all the more remarkable since people taking bisphosphonates – due to osteoporotic fracture, long-term steroid use or severe osteopenia – are just the ones you would expect to need the most revision of joint replacements. Just imagine if a cheap, well-tolerated annual infusion could halve the rate of revision joint surgery in future health systems.

Arch Intern Med  9 Jan 2012  Vol 172
41    Having been so dismissive about chronic kidney disease, I was eager to be enlightened by these follow-up data on progression to end-stage renal failure according to blood pressure in the cohort (mean age 69) from the Kidney Early Evaluation Program (KEEP). According to the authors, “The KEEP is a health screening program that attempts to raise awareness of CKD in the population.” They then demonstrate that serious kidney failure occurs at a rate of about 14% in this elderly cohort over a period of 10 years if the systolic BP is above 150 (one measurement). “Findings did not materially differ when limited to persons with eGFR lower than 60 mL/min/1.73 m2 and macroalbuminuria (ACR   300 mg/g).” From which one might conclude that one should attempt to reduce awareness of eGFR and albumin excretion. The label of CKD does nothing to inform treatment: just aim to reduce the systolic BP in your elderly patients, and you will help to prevent a lot of strokes, some heart failure, a few myocardial infarctions and a little bit of kidney failure.

Plant of the Week: Foeniculum vulgare “Purpurea”

Mention of the Greek word marathon for fennel reminds me of the excellence of this garden plant, especially in the winter months, when frost gives a magical appearance to its tufts of thread-like leaf. These plumes of icy gossamer may herald the death of the plant, which is none too hardy in cold British clay, though it has become a perennial weed wherever the summers are hot and the soil is light, as in many parts of Europe and the USA.

The bronze-leaved version is the one to grow, unless you want big bulbs to eat raw in salads or cooked in Italian dishes. It is a wonderful foliage plant, up to the point that it throws up its flower-stalks and goes to seed. The seeds should be used for fish dishes and the stalks should be kept and dried.

Fish and fennel are made for each other. It is a more delicate herb than dill, and is a superior substitute for dill in most situations, for example in making gravadlax. This is extraordinarily simple and only requires a filleted cheap salmon, salt and sugar, plenty of fennel fronds and a suitable kind of spiritous liquor, such as rum, brandy or whisky.

When cooking sea-bass in butter and wine, you should consider adding fennel-seeds (which are actually fruits); and fennel leaves make a fine decoration for the served fish.

Prometheus used dried fennel stalks to bring fire from the gods to men, and Elizabeth David waxes sternly lyrical about the Mediterranean habit of burning dried fennel stalks under grilled fish to impart flavour. I have never tried this, though I once dried a lot of fennel in readiness. The Supreme Instructress warns that the cook should exert strict control over the process, so as to avoid serving guests fish that is covered in bits of burnt fennel. Just to be awkward, I think I shall make this a special feature of the Sea-Bream “Prometheus” which I intend to serve at summer barbecues this year.

JAMA  4 Jan 2012  Vol 307
37    The gradual makeover of JAMA takes a further step with the introduction of a series of Viewpoints in the opening section. Quite nice, and very like the NEJM: it’s good to see some of America’s liveliest minds at work here thinking about medicine in general and their chaotic health economy in particular. On the latter topic, there are good contributions from Zeke Emanuel, Robert Brook and Jon Skinner, though nothing quite as trenchant as the article in last week’s New England Journal on The Savings Illusion which points out that most costs in the US system are fixed in people and institutions, and hence very difficult to shift by any means at the government’s disposal. I’m also keen to flag up the contribution here by John Ioannidis and colleagues on how slow doctors are to abandon discredited treatments: they cite PCS for stable angina, vertebroplasty for vertebral fractures, and bevacizumab for breast cancer. And they point out how crazy the current system for developing new ones is:

“Asking corporate sponsors to conduct pivotal trials on their own products is like asking a painter to judge his or her own painting so as to receive an award. If a manufacturer can be allowed to manipulate the system to create a blockbuster product from an ineffective drug, the temptation is hard to resist.”

47    It’s not just useless interventions that persist in medicine either: useless measurements seem to be even more intractable. Things like IQ or BMI that simply don’t measure anything you need to know. The body mass index takes quite a hammering in two editorials in this week’s JAMA, and this study of weight gain following overeating helps to show why. Subjects who were overfed with carbohydrate in this study could drop their BMI while gaining fat: this was corrected by adequate protein intake which promoted gains in lean mass. So people overfed with protein put on weight, but this is “good weight” in the form of muscle, associated with reduced insulin resistance and higher rates of metabolic activity. Just measuring BMI says nothing about all this: in fact here it sent entirely the wrong signal as to which form of over-eating is “healthier.” I do think the one thing we know about diet, amongst the huge accumulation of myth and rubbish, is that protein is a good form of energy intake. I’m quite in favour of fat too, but let’s not go there just now.

56    If you look at obesity measured by BMI, and then adjust for insulin resistance, hyperlipidaemia and high blood pressure, weight as such is actually a weak predictor of cardiovascular risk. Which may explain why the absolute benefit of bariatric surgery is not enormous, and is probably non-existent for obese individuals without other risk factors. This is a report from the Swedish Obese Subjects (SOS) study at a median of 14.7 years, and it shows a halving of cardiovascular events in the group treated with bariatric surgery. That sounds impressive, but absolute mortality difference actually amounts to 1.3% in favour of surgery. And the benefit was not related to baseline BMI in this study. Even longer term data are needed.

66     I have spent several afternoons over the last few months listening to presentations on readmission rates in US hospitals, wondering all the while how these compare with other health systems. For myocardial infarction, they are very high compared with other developed countries. “However,” say the authors, “this difference was greatly attenuated after adjustment for length of stay.” In other words, the facts that the US has the shortest stays for MI, and the highest readmission rates, are not unconnected.

NEJM  5 Jan 2012  Vol 366
1    The world’s foremost medical journal celebrates its 200th birthday with an account of its history which is well worth reading. It’s fascinating to note that the early decades of the twentieth century were marked by disquiet about how patients would get looked after amidst the growth of “specializm” as it was then called. “How much can the specialist know of home conditions, of family difficulties, and their relation to the case?” lamented a physician in 1923. We continue to lament. The problem of “inferior human stock” also exercised eugenically-minded physicians of those times: in 1934 an editorial declared: “Germany is perhaps the most progressive nation in restricting fecundity among its unfit. . . . In America it is probable that the sentiment of the people is not ready for the adoption of the German plan, and will be inclined to restrict compulsory sterilization to a small proportion of those who might properly be regarded as especially fit subjects of this treatment.” The subsequent history of the NEJM makes amends for this: it is even showing signs of becoming a proponent of social justice in the USA under its cloak of demure conservatism. Happy Birthday, New England Journal: do all the good you can.

9     A new era in secondary prevention after acute coronary syndrome is the headline of one birthday editorial, celebrating the success of low-dose rivaroxaban in reducing a composite end-point of death from cardiovascular causes, myocardial infarction, or stroke in 15,526 patients with recent ACS. And to be fair, this amounted to an actual (small) tally of lives saved: total mortality was reduced from 4.5% to 2.9%. It would take any competitor a comparable amount of effort to show benefit from its own fixed-dose anticoagulant, and two have already tried and failed (apixaban and dabigatran), perhaps because the dosing was wrong. Rivaroxaban also failed at a dose of 5mg b.d., but by halving this it was changed from an agent that caused too many bleeds to one which prevented more events than it caused. Good news for Johnson & Johnson and Bayer shareholders, then: but for post-ACS patients and health systems struggling to contain costs? For these, the “new era” is a mixed blessing: someone will need to interrogate the individual patient data from this vast 766-centre trial, and then we will have to wait at least a decade for evidence from trials of equal size to find out the optimal anticoagulant/antiplatelet cocktail for post-ACS patients.

20    But at least we can cross vorapaxar off the list right away: this new oral protease-activated–receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation simply caused more bleeds in post-ACS patients, without any countervailing benefit. That’s a pity: I rather like the name. (I took a shine to vorapaxar: What a shame we had to axe her).

34    Another “failed” trial: a herpes simplex vaccine which was intended to protect against HSV-1 and HSV-2 genital infection in seronegative women, but which just gave partial protection against HSV-1 at the cost of a lot of local reactions. But maybe a stepping-stone to something better.

Lancet  7 Jan 2012  Vol 379
31    Deep vein thrombosis of the leg is followed by post-thrombotic syndrome (PTS)  in about half of patients with above-knee DVT, and small previous studies have suggested that some form of local thrombolysis might help to reduce this. A team from south Norway set out to put this to the test. They used a catheter with lots of side-holes in it, rather like the nose-piece worn by the Dong with a Luminous Nose: this was inserted into the popliteal vein when possible and used to feed alteplase into the immediate environment of the clot. The reduction in PTS only just reached statistical significance and there were 8 major or medically significant  bleeding complications in the 101 patients treated with catheter-delivered thrombolysis. The investigators conclude that CDT should be considered in patients with a high proximal DVT and low risk of bleeding.

39   “This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer.” Yes, by a paltry four months and at a huge cost which is not just financial: one in twenty of the subjects suffered osteonecrosis of the jaw for a treatment which makes no difference to survival. Denosumab is a fully human monoclonal antibody that specifically binds and inactivates RANKL, the agent by which osteoclasts nibble away at bone. The obvious comparator in this trial would therefore have been a bisphosphonate, but instead it was placebo. I expect that debate about the place of denosumab in the treatment of prostate cancer will continue to rankle.

47    I fell in love with Iran thirty-eight years ago, when I went there as a medical student: thereafter I always yearned to return as a rural primary care doctor, serving some of the most civilized and hospitable people on earth. It never happened; but my longing to return was rekindled recently by working alongside a delightful young Iranian doctor at Yale. Iranian medicine is still ridiculously patchy and top-down on the American model, and few good doctors want to practice in the vast mountainous rural areas of this great and beautiful country. Since the mid-1980s, much of the primary care in such areas has been done through locally recruited assistants, like the Russian feldschers, who command one-sixth of the income of doctors. This system is known as behvarz, meaning good skill. Their skills do seem to be reasonably good in looking after diabetes and hypertension, though one is slightly alarmed to note that “Respondents were classified as having diabetes if their FPG concentration was 7 mmol/L or lower.”

BMJ  7 Jan 2012  Vol 344
If you want to know my views on the papers in this themed issue on missing trial data, all you have to do is read the editorial. For a really trenchant commentary, here is Harlan Krumholz (as posted on CardioExchange):

Missing Data: The Elephant That’s Not in the Room
Harlan M. Krumholz, MD, SM

There is a problem so grave that it threatens the very validity of what we learn from the medical literature. Bad data? Not exactly. Actually, it’s missing data — information, relevant to the risks and benefits of treatments, that is simply not published. In some cases, these data would make a critical difference in the inferences that readers draw from the literature. The absence of the data renders meta-analyses, systematic reviews, and book chapters suspect. Conclusions are made on the basis of incomplete science. In short, publication bias and selective publication are impugning the validity of what we can learn from a PubMed search or even the most careful review of published studies.

This matter demands our immediate attention and speaks to the need to rethink the configuration of clinical medical science. It may be time to adopt strategies to ensure that all relevant studies, results, and supporting documentation are made publicly available. “Out of sight, out of mind” is a dangerous reality in science and medicine. It’s time for a change — and it starts with the recognition that we have a problem.

I urge you to read BMJ this week to explore the evidence of this problem. In full disclosure, the studies include one by me (with others, led by Joe Ross) showing that more than half of trials sponsored by the NIH go unpublished even 30 months after completion. The other articles reveal troubling information, including about how missing data can affect the results of meta-analyses — and how many investigators are ignoring the requirements for mandatory reporting of trial results, raising the question of what “mandatory” actually means.

It is time to pay attention to this issue — and to begin working together to solve it. Let’s advocate for open science and get all the information out in a timely way for everyone to inspect. There are many facets to this problem, and we should not look to assign blame, but we do need to change our research and publication culture. Our entire clinical research community, including those who use the information and those who contribute to its dissemination, must collectively determine how best to get beyond this period when we are working with an incomplete view of medical evidence. Let’s put everyone on notice: The era of missing data must end.

After you review the studies in BMJ, please share your thoughts here with fellow members on CardioExchange. Links to several of the articles are provided below, with key quotations from each one.

Ross et al: Despite recent improvement in timely publication, fewer than half of trials funded by NIH are published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion. Moreover, after a median of 51 months after trial completion, a third of trials remained unpublished.

Hart et al: The effect of including unpublished FDA trial outcome data varies by drug and outcome.

Ahmed et al: Publication, availability, and selection biases are a potential concern for meta-analyses of individual participant data, but many reviewers neglect to examine or discuss them. These issues warn against uncritically viewing any meta-analysis that uses individual participant data as the most reliable.

Prayle et al: Most trials subject to mandatory reporting did not report results within a year of completion.

Wieland et al: Based on the results for 2005, at least 3000 records describing randomised controlled trials but not indexed using RCT may have been entered into Medline between 2006 and 2011.

To leave or read comments, you’ll have to visit the version that’s only open for CardioExchange members.

Ann Intern Med  3 Jan 2012  Vol 156
1     Rituals involving touch are powerful forms of social grooming, an underexplored element of the medical encounter which Michael Power drew my attention to some time ago. In any comparison of treatment for neck pain, I would have presumed that spinal manipulation would be bound to win over home exercises or medication for pain control, but in fact it proves no better than home exercise at any point in this year-long trial. Hands-on seems no better than hands-off, even as a placebo.

19    The Yale Center for Outcomes Research and Evaluation, to which I shall be returning next week, keeps an eagle eye on American hospital outcomes. This is no easy task, but Elizabeth Drye and the rest of her team have done a typically thorough and exemplary job of comparing hospital mortality figures for three conditions – acute MI, heart failure, and pneumonia – according to whether deaths occurred in hospital or within 30 days. Hospitals which discharged patients quickly tend to have an advantage in mortality statistics which disappears when you look at the 30-day mortality.

27    When I became diabetes lead for my practice a few years ago, I looked in vain for a diabetes guideline I believed in. Then came the ADVANCE and ACCORD studies, and I became increasingly puzzled and angry: how come the evidence base for treatment in type 2 diabetes was so poor, and that when large well-conducted trials were published, nobody took any notice? Why did practically every “expert” behave as if nothing had happened? Why were we adopting whole new classes of agent without any evidence about their long-term harms and benefits? I have sounded off a great deal about this since, but I am still a bit puzzled and a bit angry. So, I think, were the authors of this systematic review of  guidelines for oral treatment in type 2 diabetes. But they hide this quite well, and simply call for better standards. Yes indeed.

Ten Commandments for testing – by Michael Power
John Yudkin’s wonderful Ten Commandments for prescribing proved very popular – and they have inspired this excellent further Decalogue from Michael Power, which I send you with his permission. Please do send your feedback to hmichaelpower@gmail.com, cc. richard.lehman@yale.edu.

Thou shalt obey the following ten Commandments for testing, whether it be for ruling in a diagnosis, ruling out a diagnosis, assessing risk or prognosis or response to treatment, or for monitoring for adverse effects and deteriorating status.

Thou shalt understand testing in its broadest sense; it includes history, examination, laboratory tests, imaging investigations, diagnostic procedures, and therapeutic trials.
When a commandment is impractical or impossible, thou shalt treat it as an aspiration and do thy best.

For I am thy patient and client, whose interest thou shalt serve, and no other.

1. Evidence. Thou shalt not take the evidence in vain, but test according to the best estimates of prevalence, positive predictive value, and negative predictive value. If the predictive value of a test is less than about 50%, toss a coin — it will be cheaper and as useful.
2. Application of evidence. Thou shalt not overly rely on test results, but shalt apply your clinical judgement after clinically assessing your patient and critically appraising the evidence, taking into account its precision, risk of bias, and directness of applicability.
3. Cost-effectiveness. Thou shalt not covet thy neighbour’s graven image technology (PET scanner, fMRI scanner, high resolution ultrasound scanner), nor his micro-array genetic tests, nor his direct to consumer testing business, nor his yacht, nor any thing that is thy neighbour’s, but thou shalt practice cost-effective testing. If a cheaper test will be as useful, use it.
4. Patient-education. Thou shalt help thy patient understand that many diseases are gradual and progressive, analogue processes not digital events. Diagnostic thresholds and limits are chosen for convenience, but create artificial categories that may be misleading if they are misunderstood as boundaries between having and not having a disease, or having and not having a risk.
5. Joint decision-making. Thou shalt help thy patient understand the limitations of tests. Many conditions cannot be diagnosed or excluded by tests (for example dementia, wellness). Tests can be falsely positive or falsely negative or inconclusive. No test can give a precise prognosis for survival or other probability, and interpretation of prognostic tests should consider both the average (median or mean) and the distribution in the comparator population. Thou shalt remember that test results can in themselves be distressing or harmful. For these reasons, decisions about testing are best made jointly with thy patient.
6. Patient-centred care. Thou shalt not take thy patient’s needs in vain, but before testing help them understand what the management options are for a positive, inconclusive, or negative result, and what support is available should the result be distressing. Honour the elderly patient, for although this is where the greatest levels of risk and temptation to test reside, so do the greatest needs for avoidance of useless and harmful testing.
7. Efficiency. Thou shalt not repeat a test when the result is already available or the result will not change (as with genetic tests or when the clinical indications have not changed). Thou shalt ensure that the results of tests you have ordered or performed are clearly recorded and available or communicated to any other physician caring for thy patient.
8. Ethics. Thou shalt not use testing as a defence against legal action, or as a placebo, or as a delaying tactic while nature takes its course, or to avoid confronting the limitations of curative medicine when care, support, or palliation is appropriate.
9. Education and engagement. Thou shalt help thy trainees and junior colleagues understand that they should investigate having considered the needs of their patients and the performance of the tests. The reason for testing should not be that it is routine, or policy, or what they imagine their consultant/attending expects.
10. Gnothi seauton. Thou shalt know thy cognitive limitations and biases. Thou shalt try to avoid the fallacies of assuming that all abnormal results are important or that an abnormal result is sufficient to explain symptoms. Thou shalt consider the whole picture, and the differential diagnosis, and the possibility that tests bear false witness against thy patient.

JAMA  28 Dec 2011  Vol 306
2684    When I first became a GP in England well over 30 years ago, the early diagnosis of myocardial infarction was a matter of slight importance, since there was no intervention which made any difference to survival. You tried to reach patients in their homes quickly to relieve their pain with heroin, but only sent them to hospital if their pain was not controlled or they were going into shock: studies at the time indicated that patients with heart attacks survived better at home, where they were less likely to be killed with injections of lidocaine.

These days, by contrast, patients with chest pain are best to bypass primary care altogether and get transferred to a place offering percutaneous intervention as soon as possible: time equals myocardium. What we need most is a test to rule in myocardial infarction immediately. But what this German paper concentrates on is a test that can rule out myocardial infarction at three hours. And this test is nothing new at all: just conventional troponin 1, which proves just as discriminatory as the high-sensitivity troponin assay featured in the paper’s title. But then if you read the detail of this study of 1818 patients presenting with chest pain between 2007 and 2008, you discover that you can get nearly the same rule-out information three hours earlier if you measure either copeptin or sVEGFR-1/sFLT-1 together with high sensitivity troponin on arrival. The negative predictive value is 98.4% rather than 99.6%. Unfortunately the rule in characteristics are not so good, but I still think this is a discovery of major clinical importance, which you won’t even find mentioned in the abstract. It edges us closer to a diagnostic strategy where we could send many patients home at once with confidence, and should encourage us to develop new, more discriminatory tests to allow as many as possible of the remainder to benefit from immediate PCI.

2704    Over recent years, I’ve taken you laboriously through various studies of clopidogrel, in a personal quest to understand the importance of CYP2C19 genotype and the clinical effectiveness of this drug. To begin with, this looked like providing clear evidence of the dawn of genomic “personalized medicine,” the wondrous age in which anyone rich enough will be tested to find out if they are likely to respond to every drug their doctors prescribe for them. Because if you look at the aggregated studies of individuals with one or more CYP2C19 alleles associated with lower enzyme activity, you will find they have lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding, and a slightly higher risk of CVD events. But if you just look at the bigger, better studies, any clinical difference vanishes, as demonstrated in this painstaking systematic review. So we have come full circle; the long trail has taken us nowhere: pharmacogenomics may be about to dawn, but not just here. 

NEJM  29 Dec 2011  Vol 365
2463   Elastic stockings with graduated compression may not be the last word in sexy medicine, but they are very effective at preventing venous thromboembolism in acutely ill medical patients. So much so that adding enoxaparin prophylaxis to stockings makes no difference to mortality in such patients, while tending to increase their risk of bleeding. I am sure this cannot have been the result that Sanofi, manufacturers of enoxaparin, were hoping for when they funded this trial which recruited 8307 seriously ill patients in 193 hospitals situated in juicy potential market countries – China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia.

2473    Sometimes one almost feels sorry for drug manufacturers. Genentech developed the vascular endothelial growth factor antagonist bevacizumab which shows some action against advanced bowel cancer. Here they helped to support a trial in ovarian cancer, which typically presents at stages 3 and 4, too late for curative treatment. In a complex randomization process, some of the 1873 women recruited received placebo in addition to standard platinum-based chemotherapy, while others received one of two high-dose bevacizumab regimens. Calculating from British prices, the cost of the bevacizumab would have been about £40K per patient. The primary end-point was changed during the trial from overall survival to progression-free survival. Even with this dilution, the drug only achieved a 4 month difference, if continued beyond the duration of chemotherapy: and the Kaplan-Meyer charts in Figure 3 showing overall survival should dissuade all but the wealthiest funders from using this regimen.

2484   Another trial, this time British and partially funded by Roche, confirms the message: the incremental benefit of long-term bevacizumab on ovarian cancer is minimal. This trial included a wider group of women, some with early disease. Once again, the primary end-point was progression-free survival, and the mean difference was four months following prolonged treatment. The investigators deserve credit for stating that “Some will argue that final overall survival data are needed before the results can be fully interpreted.”

2507    We are surrounded by bioterrorists: they took over the world about 3 billion years ago and have been in charge ever since. Fortunately they have no particular interest in us, as we walk about carrying far more of them than there are cells in our bodies. Now and again, with or without human help, they turn nasty, and that is presumably why the gentle little state of Rhode Island houses a Center for Biodefense and Emerging Pathogens, source of this paper about proprotein convertases in health and disease. The New England Journal excels at telling us about these arcane and interesting subjects at the forefront of biomedical discovery: sometimes the accounts are even intelligible, as in this case. This group of enzymes does an awful lot of stuff in the body, from telling embryos to develop to helping cancer cells metastasise: but the bottom line here is that a lot of microbial pathogens hijack the proprotein convertases to produce their toxins. The family most involved are called furins, like something out of the prophetic works of William Blake: these children of the Fury of Los help to forge the toxins of germs as various as anthrax, influenza A and respiratory syncytial virus. Our protectors in Rhode Island comment,” Therapy targeted to proprotein convertases may therefore represent a universal countermeasure that could be deployed in tandem with other interventions, especially in cases of bioterrorism, in which a specific pathogen may not be immediately identified.”

Lancet
For the second week running, The Lancet has failed to appear, but for those who are getting withdrawal symptoms (e.g. relief, happiness, clearing of the mind etc), there is a wealth of material backed up on the website stretching back to January 2011. One contribution I particularly commend was posted on 1 Dec and is a systematic review and meta-analysis of individual patient data from randomized trials of self-monitoring of oral anticoagulation. Conceptually, the age of anticoagulation using vitamin K antagonists is over: were cost no consideration, everyone would by now be taking a fixed dose of factor Xa or thrombin inhibitor. But as things stand, the need for INR measurement will remain with us for at least another decade, and this study should change practice during that time, especially among younger patients taking coumarins because they have mechanical heart valves. “We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0•51; 95% CI 0•31—0•85) but not for major haemorrhagic events (0•88, 0•74—1•06) or death (0•82, 0•62—1•09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0•33, 95% CI 0•17—0•66), as did participants with mechanical heart valve (0•52, 0•35—0•77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes.” Not only a clinically important paper but a nice example of individual patient data meta-analysis too.

BMJ
The next BMJ will be a themed issue on data disclosure, about which my lips are sealed until Friday morning. But sneaked onto the website during the time warp between Christmas and New Year is an excellent piece called The Idolatry of Surrogates written by three friends – John Yudkin, Kasia Lipska and Victor Montori – using type 2 diabetes as an example.

My sole contribution was to suggest the word “idolatry” to John a good few months back. Obsessed with glycated haemoglobin and microalbuminuria, diabetologists are like the Children of Israel in the wilderness, worshipping the Golden Calf and ignoring the Voice from Mount Sinai, whose Great  Commandment is “First Do No Harm.” John went on to develop the full Ten Commandments, but was dissuaded from publishing them due to American religious sensitivities:

The New Therapeutics: Ten Commandments

• Thou shalt treat according to level of risk rather than level of risk factor.
• Thou shalt exercise caution when adding drugs to existing polypharmacy.
• Thou shalt consider benefits of drugs as proven only by hard endpoint studies.
• Thou shalt not bow down to surrogate endpoints, for these are but graven images.
• Thou shalt not worship Treatment Targets, for these are but the creations of Committees.
• Thou shalt apply a pinch of salt to Relative Risk Reductions, regardless of P values, for the population of their provenance may bear little relationship to thy daily clientele.
• Thou shalt honour the Numbers Needed to Treat, for therein rest the clues to patient-relevant information and to treatment costs.
• Thou shalt not see detailmen, nor covet an Educational Symposium in a luxury setting.
• Thou shalt share decisions on treatment options with the patient in the light of estimates of the individual’s likely risks and benefits.
• Honour the elderly patient, for although this is where the greatest levels of risk reside, so do the greatest hazards of many treatments.

JAMA  21 Dec 2011  Vol 306
2567   Amongst all the awful things that can befall human beings, poor sleep seems but a trivial inconvenience. Well, maybe: it merely doubles one’s risk of cardiovascular events and depression, and leads to undesirable effects on everyone around. In this survey of nearly 5,000 US police officers, 40% were found to have to have some form of sleep disorder, and 30% had evidence of sleep apnoea. There was an unsurprising correlation between this and falling asleep at meetings and at the wheel of a car; also with complaints from the public and administrative errors. I think the biggest improvement in medicine during my career has been the diminution in levels of sleep deprivation among doctors: at least you get the chance to sleep these days, even if you are a bad sleeper.

2588   Thiazide diuretics have been around for longer than most doctors can remember, and the thiazide-like chlortalidone received FDA approval in 1960, which is before most doctors now practising were even born. At least one large trial (ALLHAT) has shown that chlortalidone is better at reducing cardiovascular events than other blood pressure lowering drugs, though whether it is better than other thiazides we do not really know. It is certainly the logical choice for first-line treatment of elevated blood pressure, as confirmed by the long-term data from the SHEP trial which are published here. Older people with isolated systolic hypertension will on average be spared cardiovascular death by one day for each month they take chlort(h)alidone.

2608   Something terribly wrong is going on in the field of drug development. The commercial model which generated new drugs throughout the second half of the twentieth century is increasingly incapable of meeting the needs of the twenty-first. This is especially true of new drugs for cancer, the subject of this commentary piece. Spectacular advances in basic science and the genomics of cancer cell lines have produced a vast range of tempting targets for cancer therapeutics, but the net benefit to most cancer patients so far has been negligible. The current process of patenting and secretive testing, followed by years of phase 2 and phase 3 human trials, is enormously time-consuming and expensive and does not guarantee either a return for the drug manufacturer (the article quotes a figure of 0.3%) or a useful drug for the public – as illustrated by the case of trastuzumab (Herceptin). There must be a better way, involving open data-sharing from the outset rather than a scramble for intellectual property rights and patents, and Jay Bradner at Harvard has shown how it can be done.

(I wrote this before reading Robert Schwartz’s perspective piece in the NEJM. He says exactly the same, and cites a book by Philip Mirowski called Science-Mart: Privatizing American Science, Harvard 2011. Spread Christmas gloom.)

2610   Ten years ago, my GP partner Harold Hin and I got interested in the measurement of B12 levels and the whole question of what homocysteine levels really mean in the population. Harold concluded that methylmalonic acid was probably the best test of the overall metabolic effect of folic acid and B12, and did an excellent community study which never got the attention it deserved. His views are echoed in this commentary by David Spence and Meir Stampfer: it could well be that although homocysteine-lowering trials failed to lower cardiovascular events in the populations tested, there may be subgroups who benefit and these might best be identified by measuring methylmalonic acid in serum or urine. Worth re-exploring.

2612   Howard Brody and Franklin Miller write a lovely essay on the placebo effect and its essential, humane role in the medical encounter. Much of what they write about is the art of communication, empathy, and simple kindness. All the more important for that: don’t forget that these things work for patients, and help you become a better human being too. This has nothing to do with deliberately deceiving patients with hocus-pocus, but much to do with using the consultation as a therapeutic act in itself.

NEJM  22 Dec 2011  Vol 365
2357    The year ends with a milestone in medical history: successful gene therapy for haemophilia B (Christmas disease). Six patients with less than 1% of normal factor IX (FIX) activity were infused with a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein. They all began to produce their own FIX and four were able to stop prophylactic treatment and remained free of haemorrhagic episodes over 12 months. The other two needed fewer FIX injections. Had this treatment been developed a century ago, the Russian royal family would have given the discoverers ten million gold roubles and most of Poland. As it is, it would surely be right if the Nobel Prize went to a team of clinical researchers for the first time in decades.

2366   I rather struggled with this report of long-term outcomes from the Diabetes Control and Complications Trial (DCCT) and the observational study that followed it, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. The original interventional study (n=1441) aimed at reducing the HbA1c in patients with type 1 diabetes in the interventional group to little more than 6% over a mean of 6.5 years: in fact the level achieved was 7.3%, whereas in the control group it averaged 9%. This paper describes renal outcomes at a median follow-up of 22 years. Unfortunately the authors concentrate on the glomerular filtration rate rather than hard outcomes, but hidden in the text you can discover that in the tight control group, 29 subjects died and 8 developed end-stage renal failure; in the usual care group, 34 patients died and 16 developed end-stage renal failure. So in this population of young people with type 1 diabetes, there is definitely some benefit to the kidneys from tight control, but in absolute terms it is not large. 

2389    Primary hyperparathyroidism is a topic I considered for the Easily Missed series, especially since a family member was diagnosed with it and I was forced to consider whether I might have it myself. Subtle features of asymptomatic hyperparathyroidism include weakness, easy fatigability, anxiety, and cognitive impairment: just like the symptoms of being alive, really. Perhaps I should have my calcium and PTH checked; but then, on reading this review, I can’t really find much evidence that parathyroid surgery makes a lot of difference. Which is why we decided against including it in Easily Missed, and I still haven’t had my blood tests.

2398    Make your Christmas experience complete: read an update on focal segmental glomerulosclerosis.

Ann Intern Med  20 Dec 2011  Vol 155
820   I have tried to keep up with the large and confusing literature about vitamin D over recent years, and I was attracted by the title of this review: New Insights About Vitamin D and Cardiovascular Disease. The authors plod through the evidence and explain the mechanistic possibilities by which vitamin D deficiency or insufficiency might play a part in hypertension and atherosclerosis. On the other hand, vitamin D deficiency may just be a marker for not getting out much and not being able to afford the right food. More studies are needed, they conclude: and I concur, but this is not a “new insight.”

Lancet  24 Dec 2011  Vol 378
This does not seem to exist, though the last issue was said to cover only the week Dec 17-23. Perhaps the Universe now faces a Lancet gap, with unforeseeable consequences for the fabric of space-time.

BMJ  24 Dec 2011  Vol 343
A good Christmas issue but not a classic. The favourite with rapid responders seems to be the study showing that orthopaedic surgeons are both stronger and more intelligent than anaesthetists. In fact it seems to show that anaesthetists are of below average intelligence (IQ 98.4): most unfair.

Plant of the Week: The Christmas Tree

Christmas trees are best made out of plastic. Happy Christmas.

JAMA  14 Dec 2011  Vol 306
2459   The topic of stillbirth got a thorough airing in The Lancet last April, when the British press seized on the fact that our figures were as bad as Estonia and therefore a disgrace to the civilized world. In fact they are much better than those in the USA, as cited in two reports here from The Stillbirth Collaborative Research Network, and the reasons become clear as you read their findings: stillbirth rates are chiefly a function of ethnicity and hardly at all a marker of the quality of antenatal care. The stillbirth rate in this very carefully studied cohort was 14% higher in Hispanic women compared with “white women,” and 250% higher in black women. But when you ascertain the cause of fetal death by post-mortem examination, as with most of the cases described here, the causes are very similar throughout groups, and none of them are easily avoidable.

2469   A second report from the study looks at the association between stillbirth and risk factors known at pregnancy confirmation. The great majority of stillbirths are not associated with any such risk factors. No doubt a gradual increase in understanding will bring about a continued slow fall in the stillbirth rate, but there are no simple answers.

2487   For many centuries, the concept of rescue cabbage was unknown to the English-speaking world, though it was well recognized by the inhabitants of Central Europe, who would keep a barrel or two of fermented Sauerkraut or kapusta to see the household through the hungry days of late winter. Nowadays we do not use this term to refer to such elemental foodstuffs of the Northern races, but to emergency coronary artery bypass grafting (CABG) following dissection or perforation during angioplasty (PCI). This used to be quite a common event, but now happens in less than 0.5% of PCIs, so in the USA many hospitals without the capacity for CABG have begun to offer PCI. This study shows that their outcomes are as good as hospitals that can offer both.

NEJM  15 Dec 2011  Vol 365
2255   The great success of statins in improving cardiovascular outcomes was well illustrated in the long-term Heart Protection Study figures published last week, though if you look at the main figure you will see that the absolute benefit for most people is not huge. For some drug companies the patent life of these drugs meant annual profits of billions of dollars, and the last decade has seen a scramble for the next lipid-lowering blockbuster, based on the idea that the more you lower LDL-C and the more you raise HDL-C, the more you will reduce cardiovascular risk and the more you will be able to pay your executives and shareholders in years to come. But this stubbornly refuses to happen. Even if it did, the absolute benefit to most people already on cardioprotective drugs would be marginal. Niacin is a fairly unpalatable vitamin which does the right things to lipid levels and showed slight promise in earlier trials. Here in the AIM-HIGH trial it was given in a long-acting preparation alongside simvastatin (up to 80mg daily) and sometimes ezetimibe plus whatever other drugs were being prescribed to the 3414 recruited subjects with established cardiovascular disease. The trial was stopped at 3 years for lack of efficacy: in fact the rate of ischaemic stroke was higher in the niacin group. Facts are stubborn things, as John Adams said: and the fact is that statins have been shown to work, and other lipid-lowering drugs have not.

2268    Dronedarone is a drug we all wanted to succeed when it first appeared as a potential benign successor to amiodarone, the iodine-bearing anti-arrhythmic much hated by patients, endocrinologists, and dermatologists. Given to patients with intermittent atrial fibrillation in hospital, dronedarone restored sinus rhythm and reduced death or rehospitalization. The PALLAS trial was carried out under the aegis of dronedarone’s manufacturer Sanofi Aventis (rather than the goddess Athene), but far from proving that all patients with AF should take the drug, it showed that dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Perhaps Sanofi Aventis (now deprived of potential tens of billions in sales) should reread their Homer, and pay more attention to performing the correct sacrifices before naming a trial after this fickle goddess.

2287   When Jack Wennberg first started examining the irrational patterns of variation in care use in the USA, no medical journal would publish his results, which eventually appeared in the journal Science in 1973 to huge acclaim. Jack’s motto (taken from Napoleon) is that Geography is Destiny, and that what happens to you medically is determined by the facilities around you. If a hospital near you needs to keep its beds full in order to stay in profit, its beds will mysteriously fill up to the level required. Same with your physician’s appointment book. This study of Medicare admissions shows that rates of admission and readmission for heart failure and pneumonia are far more related to the characteristics of the hospitals than to any clinical characteristics of the patients. This happens when you have an oversupply of hospital beds and incentives to fill them. Researchers wishing to study the opposite phenomenon have a wide choice of locations in the UK to choose from.

2296   Catheter ablation for atrial fibrillation remains a technically challenging procedure and results depend both on operator skill and the careful selection of patients. When last seen, my only patient to undergo the procedure had had his fourth attempt. He was dramatically better whenever he was restored to sinus rhythm and he did not respond to any drug treatment that he could tolerate. These are the patients to consider – and this is the account to read if you want to learn about the procedure.

Lancet  17 Dec 2011 Vol 378
2095   Human parturition is a dangerous and ungainly affair, and we must be grateful that there are still a number of doctors who wish to be involved with it. If you want to see all that can go wrong with childbirth, there is no better place to go than the obstetrical gallery of the university museum in Bologna, full of beautiful waxworks of abnormalities which would have meant a painful death for mother and baby when they were created in the eighteenth century. Modern obstetrics is still not entirely risk-free: for example, there was one uterine rupture in this large Dutch trial of induction of labour comparing a mechanical method – inflation of the 30ml balloon of a Foley catheter in the cervical canal – with a chemical method, using vaginal prostaglandin E gel. The paper also contains a useful systematic review of all such trials, which tend to show better results with the Foley catheter method. It’s a very long time since I entered a birthing room, so I don’t know what modern practice is like, but it seems to me that the Foley method is the one of choice if you have to induce a woman with an unfavourable cervix near term.

2104   Last week we learnt that androgen deprivation therapy improves survival in locally advanced prostate cancer without increasing cardiovascular events. This study tells us that localized radiotherapy produces some additional survival benefit, though at the cost of local adverse effects. The absolute survival difference is 10% over a median of 6 years’ follow-up. The paper suggests that bowel symptoms are rarely severe, but the editorial points out that the wrong instrument was used to ascertain them. I think this is really important for shared decision-making, and needs to be looked at in the next analysis of this cohort and all future studies of prostate radiotherapy.

2112   Four authors clearly enjoy the opportunity to expatiate on the subject of allergic rhinitis in the pages The Lancet. I can’t say that I learnt a huge amount from reading this review, but it is well written and thorough and not to be sneezed at. Poorly controlled allergic rhinitis is a marker for a much increased risk of unstable asthma, which is only to be expected as it is a strong marker for atopy, though the review makes it sound as if that makes the treatment of allergic rhinitis per se a matter of some importance. The paper also introduces the concept of entopy, a local form of mucosal reactivity not linked to IgE. This must not be confused with entropy, the disturbing physical principle proclaimed in the Second Law of Thermodynamics. If you want to learn about entropy as opposed to entopy, the octogenarian genius Roger Penrose has written a book on the cosmic conservation of entropy called Cycles of Time (2010) – which has convinced me that not even Penrose really knows what it actually is.

BMJ  17 Dec 2011  Vol 343
1242   The statins were developed to reduce cholesterol synthesis in the liver by inhibiting 3-hydroxy-3- methyl-glutaryl co-enzyme A reductase. Whether this is their main mode of action in reducing cardiovascular events is still hotly debated, but it is clear that they work in other ways which have been bundled up into the obscure Greek word “pleiotropic.” For a while it was believed that statins were extraordinarily “pleiotropic” in a variety of beneficial ways. They were supposed to prevent osteoporosis and dementia and infections: but the evidence for prevention of infections is examined and dismissed in this meta-analysis of data from large randomized controlled trials. For a discussion of possible modes of pleiotropic action, see the Circulation paper by Liao on the link.

1243   Having been drawn into debate about targets in type 2 diabetes over the last three years, I’ve become aware of how pitifully little evidence we have for shared decision making with patients who bear this label. This is not for lack of effort: this paper identifies 145 risk models and scores for diabetes but muses on why so few clinicians use them. The basic problem is that they cannot overcome the deficiencies in the evidence we use to determine treatment choices.

1245   Among all the disease-mongering of the present age, nothing baffles me more than the promotion of “non-alcoholic fatty liver disease.” This is an ultrasound finding in up to a third of the population, and here a prospective cohort study from the USA determines its prognostic significance. “Non-alcoholic fatty liver disease was not associated with an increased risk of death from all causes, cardiovascular disease, cancer or liver disease.” In other words, it is not a disease at all. As a friend has said, it is of the same importance as fatty elbow disease.

Arch Intern Med  12/26 Dec 2011  Vol 171
1990   Have you got the faintest idea what advice your patients with diabetes receive from other health professionals? The chances are that these HPs have been indoctrinated by believers in tight glycaemic control and low fat diets and other forms of mythology dear to the devisers of guidelines and sellers of drugs. But this trial shows that however much of such advice is given, little of it is heeded. In this study, patients with long-standing poorly controlled diabetes (i.e. HbA1c around 9), three interventions achieved nearly the same lack of effect: a structured behavioural intervention of five 2-hour sessions; an educator-led attention control group education program, whatever that was; and unlimited individual nurse and dietitian education sessions for 6 months. The first worked faintly more than the other two.

2001   More alarmingly, the next study strove to achieve levels of HbA1c below 7% through the use of educational interventions. Fortunately it did not succeed. The authors acknowledge that the evidence for this target changed during the period of the study, and in fact they may have done more good than harm because most of the reductions were from above 8 to the mid-7s. They found that individual education sessions worked better than group education using the US Diabetes Conversation Map program.

2011   Finally, a group of low-income patients with poorly controlled type 2 diabetes was randomized to receive an educational intervention by video, workbook, and five telephone sessions. This achieved nothing at all.

2043   Scepticism about the benefits of screening mammography has been slow to catch on in America. The Dartmouth team of Gilbert Welch, Steven Woloshin, and Lisa Schwartz set out the case against in their excellent book Overdiagnosed, and here Welch and another colleague calculate the true chance that a woman with screen-detected breast cancer will have had her “life saved” by such screening. The likelihood they calculate from long-term US data is between 3% and 13%. They conclude that “Most women with screen-detected breast cancer have not had their life saved by screening. They are instead either diagnosed early (with no effect on their mortality) or overdiagnosed.”

Plant of the Week: Nandina domestica
Mid-December is a stern test of garden-worthiness, but coming back to our small plots in England we were struck by how much more there is to look at than in Connecticut at this time of year. Perhaps the champion plant is the Chinese sacred bamboo, a small upright shrub standing exposed to wind and frost on our front bank. It is too tender to survive in New England but seems pretty imperturbable here.

It is no bamboo at all but a relative of mahonia and berberis. Ours is even trying to produce spikes of white flower at the moment, something which should only happen in July. At some point these flowers turn into bright red berries. But this is not a plant you really grow for its flowers or fruits, but for its dainty habit and elegant sprays of evergreen leaf. As Graham Stuart Thomas says, “There is nothing like it.”

JAMA  7 Dec 2011  Vol 306
2331   Over the period I have been writing these reviews, rheumatology has moved from being a rather sleepy discipline to being a hotbed of innovation, largely thanks to the arrival of tumour necrosis factor (TNF)-α antagonists. Known rather quaintly as “biologicals,” these drugs inspired fear when first used because of the threat that they might increase the risk of severe infection in their recipients, as well as bankruptcy in the NHS units which prescribed them. In the USA, where this observational study was conducted, usage is less inhibited by financial constraints and has climbed steeply over the last decade. There are four large databases which permitted the investigators to compare 8,000 matched pairs of patients who received TNF-α blockers or conventional treatment. Rates of infection requiring hospital admission were the same in both. Cause for rejoicing? No, just for careful reflection, as in the accompanying editorial: conventional treatment with leflunomide, methotrexate and/or steroids is far from risk-free, and the rates of infection in the RA population of this study were much higher than in the general population, and higher than in many similar comparative studies done elsewhere.

2340   Still, there’s no doubt that these drugs often make a dramatic difference. In the case of Dutch children with juvenile idiopathic arthritis, “often” means one third of children taking etanercept, the standard anti-TNF-α agent in use there. These kids are more likely to be male, to have localized disease, and to have previously received DMARDs. Another third show a moderate response, and the others little or none. This is a national cohort study which includes all children diagnosed with JIA and treated with biologicals since 1999, and the detail of the text contains a wealth of information about infection, relapse after “cure” (happily uncommon) and much else – a gold mine for paediatric rheumatologists and interested parents of children with JIA.

2348   Going right back to the earliest gestational age compatible with survival, this US cohort study examines whether the benefit of antenatal corticosteroids extends as far back as 22 weeks. Yes it does, but the figures are grim: death or neurodevelopmental impairment in 90.5% of babies without steroid exposure, versus 83.4% after antenatal steroids had been given.

2382   A meta-analysis of randomized trials of androgen deprivation therapy in non-metastatic, high-risk prostate cancer brings good news for the increasing number of men who opt for castration (usually by regular injection of GnRH agonists) as a long term treatment of high Gleason index localized prostate cancer. Contrary to expectation, their risk of cardiovascular events is no higher than the comparator group of men with localized prostate cancer: but in fact the presence of the cancer itself confers extra cardiovascular risk. Androgen deprivation certainly reduces prostate cancer specific mortality and all-cause mortality in this group. Since localized prostate cancer is almost ubiquitous in men over 60, perhaps all men who value longevity should undergo castration around the time of retirement, though this might leave them less to do with their spare time.

NEJM  8 Dec 2011  Vol 365
2155    Open any pre-war medical textbook and half of it will be about tuberculosis. Now most primary care doctors in the richer world think they can almost forget about it; but according to this paper, about 2 billion people around the world harbour latent TB, so this insidious old enemy of mankind is unlikely to disappear as long as there are humans on earth. Starting ten years ago, the PREVENT-TB study started recruiting patients from the USA, Canada, Brazil and Spain with evidence of latent TB to see if a regimen of rifapentine with isoniazid given weekly under direct observation for 12 weeks would prove more effective than nine months of self-administered daily isoniazid. The rate of overt TB over 33 months was halved, but the investigators are modestly content to claim no more than equivalence until they have more data.

2167   Oops, it’s happened again. Bristol Myers Squibb and Pfizer funded this study of their new oral anticoagulant apixaban taken for 30 days by hospitalized high risk medical patients to prevent thromboembolism, in a double-dummy trial with daily enoxaparin by injection for 6-14 days as the comparator. But far from creating a vast new market for long courses of their new factor Xa inhibitor, they simply proved that enoxaparin is safer.

2178   Norwalk is a Connecticut coastal town which we visited because it boasts a September Oyster Festival of which we had high gastronomic hopes. We hired a car, paid a high parking fee, an even higher fee to enter the muddy fields in which the festival was being held, and then – no oysters, just a wealth of stalls offering tacky goods for sale. In fact we did eventually find a solitary stall selling oysters at the furthest end of the muddiest field, but not the 23 varieties that greet the molluscophage at the Grand Central Oyster Bar in New York. It would have been much cheaper to enjoy some there. Why am I telling you all this? It has nothing to do with the matter in hand, except for the name Norwalk as in Norwalk virus. Which actually comes not from the Connecticut town but from Norwalk in Ohio, in honour of an outbreak of winter vomiting there in 1968. Now there is an intranasal vaccine against it for the first time, which was tested on 50 volunteers matched with another 48 who received no protection. They were all then infected with Norwalk virus, and the vaccinated group got about half as much gastroenteritis as the control group. It’s wonderful what some people will suffer for the cause of science, or for the sake of eating shellfish in strange locations.

Lancet  10 Dec 2011  Vol 378
1997   Now and again, The Lancet takes us to the cutting edge of some new surgical technique, and this time it’s a “proof-of-concept study” of clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. That’s a rather grand way of describing a lavishly illustrated single case report of a 36 year old male with a tracheal cancer which would have been incurable but for the creation of an artificial trachea using stem cells from his bone marrow laid out on tubular matrix. Wonderful stuff, but don’t try it at home.

2005   I managed to spend 35 years in general practice without seeing a single case of carcinoid syndrome, or at least without managing to diagnose one. But it is not all that rare – as the editorial on this study points out, it is commoner than Hodgkin’s disease, and you can read all about it in our Easily Missed series. In some patients it can get fully as nasty as Hodgkin’s lymphoma, and less treatable. This international randomized controlled trial funded by Novartis managed to recruit 429 patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid) and gave them either just one Novartis-manufactured drug – everolimus – or two Novartis-manufactured drugs, everolimus plus long-acting octreotide. The main finding of this study is that patients loathe taking everolimus – the drop-out rate was 179 patients in both arms, leaving a combined total of just 71 at the completion of the trial. The ones taking the combination showed a five-month improvement in progression-free survival: but with a drop-out rate as high as this, I would beware of this statistic.

2013   A follow-up study of the Heart Protection Study cohort by the Clinical Trials Support Unit at Oxford shows both benefit and safety from the long term use of simvastatin in high-risk patients. “More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards”, they say in their conclusion. But why on earth do they slip in “LDL-lowering” before the word statin? We have no idea whether or not statins work by lowering LDL-C, and we have good evidence that their effectiveness at lowering cardiovascular risk is not related to their degree of LDL-lowering. Nor have any other LDL-lowering agents been shown to lower risk, though the CTSU gets a nice tranche of funding from attempts to prove that they do.

2039    As a seven-year-old I took to collecting spiders of every size and shutting them together in matchboxes: I would then release the very large spider that remained. As punishment for these youthful crimes of investigative biology, I later became somewhat spider-phobic: and the smaller ones have very good reason to single me out for revenge. This article on spider bite is not good bedtime reading for arachnophobes: widow spiders of the genus Lactrodectus are spreading around the world and there might be one here in the Northern USA which has its particular sights on me. Loxosceles species from South America are also on the move. Both lactrodectism and loxoscelism are very painful and sometimes life-threatening conditions, and there is no real evidence that treatment with anti-venom is effective. The huge spiders we now call tarantulas are pretty innocuous; in fact the fatal envenomation attributed to them by the inhabitants of Taranto probably came from a much smaller endemic species of Lactrodectus. The only cure, of course, is to dance the Tarantella: see if you can keep up with Heifetz in this public broadcast from the 1940s.

BMJ  10 Dec 2011  Vol 343
It’s amazing how little evidence you need to have before getting permission to put things into human beings. Artificial hips have been around for fifty years, ever since their inventor John Charnley experimented on himself with some of the components to test their effect on human tissues. But since then manufacturers have played around with new hip prostheses purely for the sake of getting a share in a lucrative market. This systematic review by members of the US Food and Drug Administration looks at the evidence to determine the comparative safety and effectiveness of combinations of bearing surfaces of hip implants. Basically, there isn’t any.

Ann Intern Med  6 Dec 2011  Vol 155
725    Far from the Madding Crowd, Madame Bovary, and a biography of John Adams: what do these miscellaneous works have in common? Well, firstly that I have read them all in the last few weeks, to sweeten my hours of exile; and secondly that the characters in them do a lot of walking. Moving about on two legs is really the intended default setting of humanity when not asleep: and this is what our knees are designed for. This may explain the paradox that as we become more sedentary, we experience more knee pain. Here is a fascinating report of the changing pattern of knee pain in the USA, derived from 6 NHANES (National Health and Nutrition Examination Survey) surveys between 1971 and 2004 and from three similar time-points in the Framingham Osteoarthritis Study. It concludes that “the prevalence of knee pain has increased substantially over 20 years, independent of age and BMI. Obesity accounted for only part of this increase. Symptomatic knee osteoarthritis increased but radiographic knee osteoarthritis did not.” And the cure for all this extra knee pain? Why, knee replacement surgery of course, a wonderful source of income for scores of thousands of American orthopaedic surgeons.

772    Are all second-generation antidepressants the same? Assuredly not, for those doomed to take them, but the evidence base for selecting one of them over another remains pitifully bad. This updated meta-analysis finds that there is no good evidence for any difference in efficacy between them – and this includes agents such as trazodone, bupropion and duloxetine as well as the standard serotonin reuptake inhibitors. There are some differences in known harms and onset of action. About the widespread problem of induced dependency, there is no mention at all.

Plant of the Week: Viburnum farreri

It is always a shock when December comes round and there are almost no plants of any kind worth looking at: and it is even worse here in New England where the Himalayan species brought back by the great British plant-hunters a century or more ago cannot survive the severe winters. Readers will be aware of my fondness for Reginald Farrer, who died alone in the mountains of northern Burma in 1920 while seeking new treasures for our gardens. His name is commemorated in this tousled shrub which looks a mess all year, but then produces white or pink flowers of lovely scent just as Christmas is bringing its hallowed season of unease and expenditure to the population of Great Britain. It is a must for every garden, to be tucked away somewhere to hide its summer ugliness; but never so inaccessible that you cannot get to smell it, and to cut some branches for the house to breathe perfume amongst the holly and the ivy. Most Americans cannot do this, but we can and will on our return to England this week.

Arch Intern Med  28 Nov 2011  Vol 171

1879         Recitative (Dido):
Thy hand, Belinda! Darkness shades me -
On thy bosom let me rest;
More I would, but Death invades me;
Death is now a welcome guest.
Aria (addressed to Aeneas):
When I am laid, am laid in earth,
May my wrongs create
No trouble, no trouble in thy breast;
Remember me, remember me;
But ah! forget my fate.
Remember me, but ah! forget my fate.
http://www.youtube.com/watch?v=iTV6F3lTU7o

American patients with myocardial infarction who are taken to a hospital without a facility for percutaneous intervention might wish to sing this lament while they wait for an ambulance to take them to a more suitable facility. This process is called DIDO (door in door out) and according to US guidelines it should take less than 30 minutes. And so it does, in 9.7% of cases, according to this survey by the Yale CORE team and others. In nearly a third of cases, the DIDO time exceeded 90 minutes. Perhaps non-PCI hospitals should simply employ more nurses called Belinda and abandon the DIDO target. There are, after all, well over 50 musical compositions called Didone abbandonata; and you might be wise to upload these on to your i-pod to listen to while the morphine takes effect and you expire on Belinda’s bosom.
http://www.youtube.com/watch?v=vuXoO5yB8LM

1894   Chronic disease management for tobacco dependence is the name given here to a telephone support intervention to promote smoking cessation, which achieved a 30% quit rate at one year compared with 23.5% with usual care. I’m really perplexed by the American fondness for giving things labels that don’t quite fit. Why call this chronic disease management? Why even think in these categories? Why not call this by its proper name of nicotine addiction, and treat it according to the well-established principle of harm reduction? You need people to stop smoking because it’s the smoke that kills them, not the nicotine or the tobacco leaves. On to the next study.

1901    We know that one moderately useful approach to smoking cessation is nicotine replacement therapy and I don’t know of any reason why people can’t stay on it as long as they feel a need for nicotine. We prescribe methadone maintenance to stop people suffering the harms associated with obtaining illegal opioids: so much more should we do everything we can to stop people killing themselves as a by-product of needing a fix of harmless neurotransmitter. In the USA, nicotine replacement products are fearfully expensive – more than three times the UK cost. In this trial they were given free to smokers who were not inclined to quit, and sure enough, while they had the free NRT, a few did quit; and then mostly relapsed. Societies wishing to encourage universal smoking cessation should ensure that lozenges containing nicotine cost the same as cough lozenges containing menthol, while racking up the price of tobacco. Doctors need not have much role in any of this.

1920   For decades, tight glycaemic control in type 2 diabetes has been preached as the best means of preventing cardiovascular complications, especially those classed as “microvascular.” The ACCORD and ADVANCE trials published in June 2008 should have blown this myth to pieces, but these large long-term studies were followed by an eerie silence from the diabetology community, which was firmly wedded to a “lower-the-better” model based on extrapolations from risk plots. Most doctors still cling to the delusion that allowing a person with T2DM to run at a glycated Hb level above 7% is sloppy medicine. On the contrary: this Canadian observational study of renal outcomes in diabetic patients with eGFR <60 provides more confirmation that the optimal HbA1c for the general 2 diabetic population is about 7.3 using current modes of treatment. Pushing it lower risks more harm than gain.

NEJM  1 Dec 2011  Vol 365
2055   Amongst the many mild culture shocks of living in the USA is the fact that you cannot walk more than about 200 metres in any built-up area without encountering illuminated letters of brown, pink, and yellow announcing an outlet of Dunkin’ Donuts. But surely not in the pages of the New England Journal! Well, admittedly it’s in their usual sober black designer typeface, but here is a study “Supported in part by a Dana–Farber Dunkin’ Donuts Rising Star award.”  And no, it’s not about the cardiovascular benefits of regular consumption of fatty pastry covered in sugary gloop: it’s about Interleukin-2 and regulatory T cells in graft-versus-host disease. This is not a theme on which I am usually apt to wax lyrical, but having touched on it a couple of weeks back, I am sure I must have whetted your appetite to learn more. You may remember that astonishing study where T-cells were fitted up with a chemical receptor that meant they could be used to kill off malignant cells, but as soon as they started to cause GVHD by attacking normal cells, they themselves could be killed off by a single injection of the antidote chemical. A sort of self-destructing magic bullet. This study is nowhere near as elegant, but probably much easier to apply to the many thousands of patients who suffer GVHD as a result of non-autologous bone marrow transplantation. The intervention was a daily injection of low-dose interleukin-2, and it resulted in remission of GVHD in about half of patients whose disease had failed to respond to steroids.

2078   Perhaps in atonement for all the profits it has made from reprints sold to pharma companies, or just from a playful sense of Schadenfreude, the New England Journal is giving everyone free access to a study which proved the opposite of what its sponsor, Astra Zeneca, hoped to demonstrate. Rosuvastatin, the Astra Zeneca “superstatin” was pitted against the “less powerful” and generically available atorvastatin. In fact this trial (SATURN) was a nasty case of comparing one set of surrogate measures (LDL-C lowering, HDL-raising) to another surrogate measure – coronary atheroma by intravascular ultrasound. That sounds awfully important, but we cannot be sure what it really means. The true relative benefits of these statins could only be properly demonstrated by huge, lengthy studies using end-points such as death and myocardial infarction. Given the margin of absolute benefit likely to emerge, such trials would be a complete waste of time and money: like most lipid-altering trials since the original statin studies of the 1990s.

2089   A thoughtful medical student wrote to me last week to ask my views on the future of genomic medicine, given the sceptical tone (to put it politely) that I often adopt in these reviews. Let me put it bluntly: if you are likely to get ill and/or die within 30 years, it’s pretty unlikely that you will see any benefit from the effort and resources currently going into genomic medicine. I don’t altogether grudge the eventual benefit to posterity but I do grudge the diversion of resources from clinical research which could benefit millions of people in the short and medium term. I’m filled with wonder and delight when genomics is applied with success to investigating the characteristics of cancer cell lines so as to develop tailored treatments: yet I still worry about the generalisability of these expensive and super-sophisticated methods. If you’re interested in the Genomics of Cardiovascular Disease, the NEJM here very kindly offers you a free guide: most of the article is taken up with hypothesis-generating associations which may or may not reveal new pathways and hence new interventions for CVD, given another decade or three. The only triumphs which have yet emerged are the alleles which govern the platelet response to clopidogrel, and those which might perhaps govern the therapeutic effect of beta-blockers in some patients with heart failure. For a brief and trenchant summary of what genomic medicine is likely to achieve, you still can’t do better than read Trish Greenhalgh’s 2005 RSM piece.

2110    Systemic lupus erythematosus is the subject of the other NEJM review. The very complexity of this account demonstrates how little we really understand this nasty and often devastating disease, and the dry conclusion doesn’t promise any imminent breakthrough:
“SLE is an autoimmune disease that predominantly affects women and typically has manifestations in multiple organs. Immune-system aberrations, as well as heritable, hormonal, and environmental factors, contribute to the expression of organ damage. Immune complexes, autoantibodies, autoreactive lymphocytes, dendritic cells, and local factors are all involved in clinical manifestations of SLE. Biologic therapies and small-molecule drugs that can correct the aberrant immune-cell function are being developed in the hope that they will be more effective and less toxic than current treatments.”

Lancet  3 Dec 2011  Vol 378
1917   “The global burden of disease attributable to seasonal influenza virus in children is unknown” we are told at the beginning of this 47 author paper. Not so much unknown as unknowable, I would have thought, since so many different viruses cause indistinguishable flu-like symptoms and respiratory disease in children; and even in the developed world we rarely carry out virological tests. Nonetheless the formidable team of investigators press ahead and reach conclusions which they think may be only 30% inaccurate. Global surveys of this kind are one of the few admirable features in The Lancet, but you do sometimes wonder what they are meant to achieve.

1940   I suppose that if you are a designer of electric kettles, your whole future depends on tweaking the design of a device which reached a perfectly satisfactory stage about 50 years ago. It’s getting to be the same with designers of coronary stents: in days gone by they had an exciting time fiddling about with new immune modulating ingredients, but now all they can do is fiddle about with permanent versus biodegradable polymers. At four years, there was no difference in outcomes. It’s so exciting, being back in the Stent Wars.

1949   Possibly the main reason we read reviews of uncommon, nasty, and untreatable conditions is that we might glean some scraps of hope to convey to our patients. My last patient with idiopathic pulmonary fibrosis died in 2000, the year I retired from my practice, so I won’t be seeing another one through to the end: though since the mean age of onset is 66, there is still time for me to get it myself. The scrap of hope here is that we are at least getting nearer to understanding the mechanism of fibrosis: not a non-specific inflammatory process but one specifically mediated by abnormally activated alveolar epithelial cells. The best hope for the future is to find something that will de-activate these cells; failing that, to deploy stem cells to recreate damaged lung. As things stand, mean survival from diagnosis is three years.

BMJ  3 Dec 2011  Vol 343
“Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.” Just the latest in a long line of such reviews, confirming what was perfectly obvious by early 2009, when I wrote a BMJ editorial on the subject with Harlan Krumholz. That said, I think this is the most thorough analysis so far: but the headline message hasn’t changed at all. For the great majority of T2DM patients, tight control has no benefit. There could still be a subgroup of people who might benefit, but we don’t know how to identify them.

For reasons I won’t try to explain, I developed a dweebish interest in the prognostic value of cardiovascular biomarkers some years ago. It struck me then, and has struck me ever since, that the only one with rock-solid predictive value is B-type natriuretic peptide and most of the rest might as well go in the bin. This study doesn’t address this issue directly but rather compares predictive values derived from observational studies with the values found in randomized controlled trials. The observational studies tend to exaggerate the usefulness of makers in many cases, including BNP: but it remains considerably better than the rest in absolute terms.

A really excellent clinical review of arthritis of the base of the thumb tells you all you need to know about this important cause of pain and functional disability – mostly but not solely in elderly patients. Splinting and exercises have a place, and so does injection with a steroid: the evidence base isn’t ideal, but injections provide relief in about 75% of cases, and don’t appear to do harm. Trapeziectomy is usually the operation of choice if non-operative methods fail.

Plant of the Week: Daphne bholua “Jacqueline Postill”

It is time that I indulged in my annual celebration of this most indispensable of shrubs, covered in leaf and flower and filling the air with the most heavenly scent throughout the gloomiest months of the year. In most British winters it stays in leaf and flower well into March, but the violently cold weather a year ago completely denuded our 2 metre-high specimen. By May there was no sign of life in the plant and we gave up hope. Two younger specimens of a white-flowered cultivar that we had recently planted out were definitely stone dead.

But then a tiny green shoot appeared near the base. We left the most treasured plant in our garden and went to the USA in June. Now it has sprouted a mass of new leaves, and when we return next week we hope that there might be just one or two flowers to remind us of past blessings, and perhaps many more to come.

JAMA  23/30 Nov 2011  Vol 306
2221   “There is a fifth dimension, beyond that which is known to man,” intones Rod Serling in accents strange, “…we call it The Twilight Zone.” Fans of the 1950 series will enjoy this week’s episode, where a bewildered reviewer finds himself in a parallel universe where he is doomed to read the same studies over and over again. Sitting at a bare table, his fingers move listlessly through straggles of unkempt hair as he opens a journal strangely like the JAMA he once knew. His narrowed eyes fall on the first paper. He removes his spectacles, wipes his brow, and peers more closely. The date on the page is November 2011! And yet the paper is still about what clopidogrel dosing does to platelet function tests… there must be some mistake. Surely this is the same paper he read ten years ago, before he … O what is happening? Mary-Lou, are you in the labratory? Where are you, Mary-Lou?
2229   Back among that which is half-known to man, the effect of salt intake on cardiovascular events is amongst the most fiercely debated. Salt restriction lowers elevated blood pressure, say the zealots, so it must reduce cardiovascular harm on a population level. Nonsense, say the sceptics: BP is a surrogate, the effects are small, and compensating mechanisms may well work in other directions. Look at all the studies that show no effect or adverse effects. Pah, say the zealots, look at all the better-conducted positive studies. Could both camps actually be right? The only way would be for the sodium-harm relationship to be U-shaped: and that is just what it proves to be in this analysis of sodium excretion in two large observational studies. The ideal daily intake is between 3 and 6G per day, judging from a single estimate of excretion: but this debate is far from over. We need better prospective studies, with regular measurements of sodium output. So if your bewildered reviewer opens a JAMA in 2021 and finds another study of sodium excretion and cardiovascular events, he won’t need to cry out for Mary-Lou.

NEJM  24 Nov 2011  Vol 365
1959   Two recent papers in the British journals appear to have settled the question of obesity management in primary care decisively in favour of Weight Watchers. But now two papers in the USA’s leading medical journal open up the field once more. What if it could all be done quite effectively over the telephone? That’s the intriguing prospect offered by this study in a real-life American population of significantly obese (mean BMI 36.6) participants, 41% black, mean age 54, and all with at least one cardiovascular risk factor. Over two years, controls randomized to self-management lost 0.8kg; those who received telephone support lost 4.6 kg; and those who received in-person support lost 5.1kg. So telephone advice and encouragement less than once a month seems to be almost as good as individual and group sessions plus remote support on tap, and very much cheaper and more convenient. Watch out, Weight Watchers.

1969   The second trial is less compelling. The study population was roughly the same, but the interventions here were usual care, brief lifestyle counselling, or enhanced counselling with the use of drugs (sibutramine, orlistat) ad libitum. The last group did best with a mean loss of 4.6kg at 2 years. Phone calls, which achieved exactly the same in the first trial, still seem like the best bet to me.

1980   You probably don’t much care, but cardiologists are still doing trials of various blood-thinning agents for use during percutaneous coronary interventions, in this case for non-ST elevation myocardial infarction. One lot received bivalirudin, and they did as well in terms of recurrent infarction or the need for urgent revascularization as the lot who received abciximab and unfractionated heparin, who bled more. So a win for bivalirudin. Strange how these names, which seemed so odd and exotic a few years ago, now seem quite passé.

1990   Now here’s the gem of the week: a meticulously designed and conducted study showing that daily low dose inhaled steroids are no better than high dose inhaled steroids at the first sign of respiratory symptoms in toddlers and pre-school kids who get wheezy when they get upper respiratory infections. The intervention was inhaled budesonide and the outcome measure was number of episodes requiring oral steroids. Reading the first part of the paper, I was again struck by the flimsy nature of the evidence that led “experts” to tell us that we should give pointless and potentially growth-suppressing continuous treatment to such a large swathe of the pre-school population. It is time to stop doing this.

2002   A survey of US hospital emergency room attendances provides a salutary reminder of the drugs which get older people admitted to hospital. All such surveys have the same top four winners: warfarin, insulin, aspirin, and oral hypoglycaemics. Opioids, benzodiazepines and “high risk” medications trail by a long distance. Digoxin gets a significant place in the American league, but I hope not the British, since I can’t think of any good reason to use this drug at all. Half of these patients are over 80. You may have to give warfarin or aspirin to a good many of them for stroke prevention, but do you really need to give many 80-year old diabetic patients sulfonylureas or insulin?

Lancet  26 Nov 2011  Vol 378
1847    Back in The Twilight Zone, our bewildered reviewer searches the laboratory for Mary-Lou, but finds only cobwebs and a coffee mug with dried mould at the bottom. He sits down again at the bare table in the empty room, but the journal that lies there is no longer the NEJM but The Lancet. When he last opened a Lancet ten years earlier he read about encouraging results from Phase One studies of stem cell implantation to regrow damaged myocardium. But this Lancet bears a date of November 2011! What can have happened between? Opening the shiny pages of unfamiliar typeface, he wipes his brow again. A phase one study of stem cells to regrow damaged myocardium…much promise…improved ejection fraction…longer studies needed… A fly lands on the page, and then buzzes away. The parking lot outside is full of dust.

BMJ  26 Nov 2011  Vol 343
Here is the much-publicised systematic review that claims to show that cereal fibre and whole grains protect against bowel cancer, whereas fibre from fruit and vegetables does not. This seems a bit odd to me, but I cannot possibly interrogate the evidence in the way that these authors have. On first principles, I would have thought that eating fruit and vegetables was bound to have some protective effect, since they contain salicylates and we know that salicylates prevent bowel cancer. Eating muesli and grainy bread has never much appealed to me; nor has the whole idea of organizing my diet to prevent some disease or other. One of the authors is a Dutch “professor of diet and cancer”, a most regrettable position. Eat what you enjoy and take your chances, say I: you will never get out of this world alive.

Which brings us neatly to the subject of successful ageing. To me, successful ageing would mean doing as much as possible that is both fun and useful in the time left, followed by dropping dead at an appropriate moment. It strikes me that one of the biggest factors that prevents successful ageing in the USA is health anxiety and the potential cost of illness, despite Medicare coverage. This American trial tried an intervention called “integrated care” which bears a striking resemblance to a more sophisticated intervention known to the British as general practice. The main difference was freer use of a depression questionnaire. People in the intervention group got more drugs for depression, cardiovascular risk factors and diabetes. What happened to them after that is anyone’s guess. At the start of the study their mean age was 57. At the end of the study it was 58.

Plant of the Week; Spinach

Once again, I am relying on the good offices of Eric Larson, the ebullient and sagacious keeper of the Yale Botanical Garden, for this week’s botanical instruction:

This week’s plant is also growing in the Marsh Gardens greenhouse, but not in our diversity collection. We have a large number of spinach plants that one or more classes use in discussing plant evolution. Spinach is one of the minority of species in the plant kingdom that are dioecious. This term that, according to my spell-checker is not in the dictionary is from the Greek. Roughly translated, it means “two houses,” which means that sexual propagation requires two separate plants, one being male and the other being female.

Most plants, as in last week’s chocolate tree, bear flowers that have male pollen-bearing structures and female seed producing capabilities. This arrangement is referred to as monoecious. Dioecious plants, although in a minority, are not rare. Other plants with this arrangement include Hollies and marijuana. There are some instances where a plant will have a little of both. These are referred to as polygamodioecious. When under certain environmental stresses, a plant that is normally dioecious will revert to monoecious to ensure that it propagates itself. Marijuana is a good example, partially because it is an annual plant, which means it germinates from seed, matures, flowers, and sets seed within a calendar year. Plants that rely on seeds alone to propagate (as opposed to forming stolons, bulbs, or other vegetative reproduction) will revert to a hermaphroditic form to make sure that they do so. Of course, extensive research has rewarded the author in his pursuit of these anomalies.

(RL’s note: I believe that the author must be referring to his liking for spinach, though one is puzzled by his frequent references to marijuana.)

Spinach is such an ancient plant in terms of its relationship with man that we don’t have a clear idea what part of the world it is native to, although one reference mentions Iran. The Latin binomial for spinach is spinacia oleracea. The genus name derives from the Latin spina, probably referring to the spiny seeds of all of the members of the genus, and especially spinach itself. The specific name also derives from Latin, meaning “vegetable, of kitchen gardens.” The family is chenopodaceae, or the goosefoot family. Other members of this rather small group (250 species)
include orach, lamb’s quarters, goosefoot, pigweed and beets.

Spinach is an annual plant, prefers cooler weather, although hybridization has resulted in some varieties that tolerate heat, and even long day length. Most Spinach varieties bolt, or send up flower scapes, as the days lengthen in June, or when the weather is hot. This is in keeping with the assumption that, when under stress, plants try to propagate themselves.

Spinach really prefers a neutral or even slightly alkaline soil, which requires some care here in the East: relaxation of the clean air act means that more acid rain is headed our way from Midwestern coal-fired electric generating plants. Soil tests, free from the Connecticut Agricultural Station right here in New Haven, should be done on your garden soil every year. Most garden vegetables prefer a soil that is within a few points of neutral (7 on the scale from one to fourteen, one being about like hydrochloric acid and fourteen being like fresh lye soap).

Spinach is a heavy eater, meaning the overall availability of nutrients in your soil should be high, with Nitrogen, Phosphorus, and Potassium being the macro-nutrients, and a long list of micro-nutrients behind. I prefer using organic means of fertilising, when necessary, which means using manure or other compost for most of the Nitrogen plants need, along with bone meal, wood ashes, green sand (a marine deposit) and other like materials to feed the soil. This is important, folks. Feed the soil, not the plants. The relationship between the soil biota and plants is complicated and complex, with no sure answers at hand. But one thing is for sure that if we approach the nutrition of plants like many people approach nutrition of people (that is, just look at the chemical composition, the place on the food pyramid and no more) then we are overlooking a major part of the chain of biotic interplay, or what makes gardening sustainable. For more on this, I invite you to get in touch with Josh Viertel and Melina Shannon-DiPietro, who manage the Yale Sustainable Food Project.

Spinach should be started by seed in the ground as early in the spring as the soil can be worked. Raised beds are ideal for spinach cultivation for this reason, because they dry out and warm up quickly in the spring, making them easier to work and not damage the structure of the soil. Try several varieties of spinach to find one that works for you. As I mentioned earlier, there are varieties that will survive summer weather much better than others, and there are some with more wrinkled leaves, some with less wrinkles, some with a different flavor.

Start harvest as soon as the plants have three sets of true leaves, and even before if you have planted them thickly. Young tender spinach is one of God’s gifts to rabbits, groundhogs and humans. Succession planting, or planting every ten days, will help to prolong the harvest. By late May or early June it is almost not worth the effort, as they bolt to seed right away, becoming bitter in the process. So, after the Ides of July, start planting again, right up until mid-September, or later if you have row-covers or a cold frame to grow them in.

Plant of the Week is a publication of the Marsh Botanical Gardens. Opinions expressed herein do not reflect on the official policies of Yale University. Contact: Eric Larson (eric.larson@yale.edu)

JAMA  16 Nov 2011  Vol 306
2099    Steve Nissen became something of a hero of mine when he showed how bad data from pharma-funded studies had been used to mask the fact that rosiglitazone (Avandia) was harming diabetic patients while lowering a surrogate end-point – blood glucose or glycated haemoglobin. But here he is leading a pharma-designed and funded study which shows that a particular drug – evacetrapib – improves a surrogate end-point, HDL-cholesterol, without any data about long-term harms or benefits to patients. The abstract concludes “The effects on cardiovascular outcomes require further investigation.” Since this drug exists to affect cardiovascular outcomes, and this trial tells us nothing about them, I cannot understand what it is doing in a leading medical journal. But there seems to be a huge amount of investment in this class of drugs – inhibitors of cholesteryl ester transfer protein (CETP) – despite the fact that the first to be licensed, torcetrapib, actually worsened CV outcomes, and was rapidly withdrawn. To think of “High-Density Lipoprotein Cholesterol as the Holy Grail” (title of editorial) is a recipe for sipping out of poisoned chalices: we should simply wait for the evidence from adequate studies using meaningful outcome measures.

2110   The discovery in the 1990s that bone marrow cells could differentiate into cardiac myocytes and repopulate damaged myocardium offered hope of a revolution in the treatment of myocardial infarction and heart failure. A number of trials published over the last decade have proved the concept but failed to benefit patients in any significant way. Marrow cells given early following percutaneous intervention for MI do grow enough new myocardium to improve the systolic ejection fraction in the treated group, but given later at 2-3 weeks post-infarct they do nothing, as this study shows. The editorial calls for better surrogate markers – but I think it is time we judged this treatment by changes that patients can notice.

2120   Reverse epidemiology is an intriguing paradox in heart failure: the fattest patients with the highest lipids survive the longest. Here’s evidence of the same phenomenon following first myocardial infarction: the higher your cardiovascular risk score, the better your immediate survival. Yes, I did read this properly: this is no case of raw Brussels sprouts. Looking at over 2 million patients admitted to US hospitals between 1994 and 2006, the investigators found an in-hospital mortality of 15% among those with no CV risk factors and 3.6% among those with a top score of 5 risk factors: and a convincing spread in the area between. Something strange is going on here: ischaemic preconditioning, perhaps.

NEJM  17 Nov 2011  Vol 365
1863   News of a partially successful malaria vaccine has been circulating for months: here is the first report from the RTS,S/AS01vaccine trial conducted in 7 African countries with 15,460 children as participants. This vaccine has the potential to reduce incident malaria by one third to one half. A big step forward, then, but overshadowed by more recent news of the discovery of a definitive vaccine target which may eventually lead to the complete eradication of malaria. About time too.

1876   The plump boy chosen by Peter Brook to play Piggy in the 1963 film of William Golding’s Lord of the Flies grew up to be quite lanky. Obese children do not have to grow up to be obese adults. Most do, sadly, and then they run high risks of diabetes and cardiovascular disease; but this analysis of four Finnish cohort studies shows that the lucky Piggies who cast off their childhood corpulence have the same cardiovascular risk as adults who were never fat.

Lancet  19 Nov 2011  Vol 378
1775    The most notable feature of this week’s Lancet is a letter with 41 signatories from the breast screening establishment attacking what they see as “an active anti-screening campaign orchestrated in part by members of the Nordic Cochrane Centre.” They accuse this campaign of being largely designed to back the prejudices of Peter Gøtzsche, citing the Lancet paper in which he first raised these concerns in 1995. At the end of their letter, they define themselves as “The signatories below, charged with provision and implementation of breast screening in many different countries” and then say “We declare that we have no conflicts of interest.” Hmm. Where is the invited response from the Nordic Cochrane Centre? Is this matter to be decided by an exchange of accusations or a debate based on the science? The modern Lancet, as so often, seems to prefer the age-old solution of a declaration by authority figures who know they must be right. How deluded the radical Thomas Wakeley was in 1823, when he set up The Lancet to question medical orthodoxy. It was all so much simpler when we had four humours, purging and leeches.

1779   We don’t know the cause of multiple sclerosis, so newly developed treatments target the inflammatory mechanisms instead. The same is true of many other conditions, such as psoriasis, rheumatoid arthritis and inflammatory bowel disease; and this approach has had a measure of success. Ocrelizumab targets B lymphocytes, specifically the CD20 B cells which can produce auto-antibodies in the central nervous system. This phase 2 trial proves the concept by demonstrating an enormous reduction (96% at the highest dose) in gadolinium-enhancing lesions on MRI in remitting-relapsing MS patients treated with ocrelizumab. So another surrogate success with uncertain meaning for long-term disability in MS. And for once the editorial does not indulge in hype, but soberly reviews this increment of possible progress in the context of other, half-proven treatments for MS.

1788    A primary care study from London and Bristol shows that GP practices which have received a training and support package on detecting and referring cases of domestic violence do indeed detect and refer more domestic violence. The size of the problem is huge, and it would be good to be certain that the interventions available are effective, on both an individual and a societal level. I couldn’t find the evidence in this study, but that was not its purpose: I just hope it exists.

BMJ  19 Nov 2011  Vol 343
In a very few years I shall be officially geriatric, and I guess my risk of emergency hospital admission is increasing all the time. Naturally I shall make every attempt to get out as soon as possible, so if you see a balding figure in a bed-gown trying to run down the street with a drip stand still connected, hail a taxi and call my wife. This systematic review tries to make the case for a complete geriatric assessment (CGA) before every hospital discharge from age 65 upwards. Outcomes tend to be better after discharge from wards where CGAs are routine. Make of that what you will: I can’t see how it makes sense to assess everybody in the same way on the basis of age alone, but maybe I’m getting touchy on the subject.

These are heady times for the commercial UK weight loss organisation called Weight Watchers. They paid for a trial recently published in The Lancet which showed that they were superior to an NHS weight loss referral programme. Now the BMJ has published an independent trial comparing Weight Watchers with two other commercial providers and an NHS provider, and again it proves to have the best results at one year (mean 4.43kg reduction). In both studies the intervention length was 12 weeks, but in this trial, unlike the previous one, there was a significant number of subjects with BMI>35.

Arch Intern Med  14 Nov 2011  Vol 171
1804    Though I usually maintain a discreet silence as I sit in on the deliberations of the center for outcomes research and evaluation, America’s foremost cardiovascular outcomes research unit, I have gained something of a reputation for my incredulity at the vagaries of the US health system. Here Brahmajee Nallamothu, looks at the phenomenal rise of carotid stenting in the USA, despite a wholesale lack of evidence of superiority or even equivalence to carotid endarterectomy. So who is doing all these unproven procedures, and why? The simple answers are: cardiologists; because they get paid per procedure, and they are used to putting stents in arteries. This has even been given a name: the oculo-stenotic reflex.

1831   We are used to think of hip fracture in frail elderly women as a common precursor to death, but this need not be so in healthy older women. To be sure, their mortality risk is higher in the short term after surgery, but by one year it has returned to baseline, according to this prospective cohort study.

Ann Intern Med  15 Nov 2011  Vol 155
653    A Canadian trial looks at the safe interval for INR testing in patients on warfarin whose INR has been in the target range for 6 months. It’s a nice study which used sham INR results in the group being tested every 12 weeks rather than every 4 weeks. “The proportion of time that patients were within the target INR range and adverse events did not significantly differ between the groups. Longer monitoring intervals may be reasonable for selected patients receiving warfarin.” – a useful finding, which confirms the result of an earlier British trial.

660   Post-hoc subgroup analysis has got itself a bad name, but performed carefully, and then tested prospectively, it may offer a route to better decision-making with individual patients. Take the case of anticoagulation to prevent stroke in atrial fibrillation. The CHADS2 score was devised to stratify risk in AF patients not taking oral anticoagulants. But here the investigators of the RE-LY trial comparing warfarin with dabigtran use the CHADS score to take a look at the relative risks of stroke, bleeding and death in all arms of this trial, where overall the various regimens produced very similar benefits and risks. The CHADS score predicted all these events in these groups too, with bleeding risk keeping track with embolic risk in the warfarin group, but less so in the patients given dabigatran. In other words, in the riskiest patients, dabigatran rather than warfarin might be the safer treatment. This analysis was funded by the manufacturers of dabigatran, but I think this is a reasonable presumption until the hypothesis has been tested further.

Plant of the Week: Malus domestica

I grew up in a terraced house in Lincoln, with a crowded little garden at the back, overshadowed one side by a neighbour’s huge apple tree. This bore fruit of unearthly size and flavour: the apples were simply too large for childish teeth to get easy purchase, and so juicy that their sap ran down one’s chin in the attempt.

I have often wondered about stealing back to get a cutting, should the old tree still be there. It’s relatively easy – so I’m told – to graft cuttings on to dwarfing rootstock and get fruit within two or three years. But maybe it would taste nothing like those fabled apples of Lincoln autumns in the 1950s.

I came to the USA expecting to encounter pulpy, flavorless (sic) apples of the kind which are imported from the hotter parts of America by British supermarkets. What a pleasant surprise to find that the apples of New England are fully the equal of any to be found in the old country, and frequently superior. Presumably they mostly came over from England in the seventeenth and eighteenth centuries, by which time there was already a great profusion of varieties. Some taste like firmer varieties of the Worcester apple, while others – o bliss! – taste exactly as I remember the Lincoln apples of my childhood. These are huge, crispy local apples, wonderfully sweet and juicy but without any little stickers to give away their name. The nearest cultivar I have found here is called Honeycrisp.

It is said that there is an apple for every microclimate, so that there can be no general rule for the selection of a variety for your garden. I used to have a garden with an old tree of Blenheim Orange, a triploid variety raised just 20 miles distant and once very popular in England, until hybridized by Cox with the Ribston Pippin. Cox’s resulting Orange Pippin is less aromatic and characterful, but much more reliable. But it is of course a mistake to grow in your garden a variety which is always available in the shops.

We have gone one worse and have in our garden a tree grown from the pip of a Golden Delicious apple. For sentimental reasons, it can never be extirpated; and unfortunately its fruits are true to type, neither golden nor delicious but scabby and tasteless. However, an apple tree of any kind has many garden virtues: it produces lovely blossom in the spring, and its roots seem to encourage the growth of morel mushrooms, should you be very lucky. And a fully grown apple tree is an excellent framework for a vigorous climber, such as viticella clematis or even wisteria.

JAMA  9 Nov 2011  Vol 306
1983   Replumbing the brain through a hole in the skull is an idea that sounds straight out of the heroic days of kill-or-cure surgery. It’s been known for about 50 years that you can connect the superficial temporal artery branch through the cranium to a middle cerebral artery cortical branch, and so restore the middle cerebral blood supply if it is impaired, usually as a result of carotid artery stenosis. You can imagine old Harvey Cushing devising this operation in his glory days at Yale, except that he didn’t. There was a big trial in the 1980s which failed to show any benefit, but this new trial tested the possibility that with modern brain imaging it might be possible to identify a high-risk subgroup of people who might benefit from the procedure. Advanced PET imaging was used to select the patients with impairment of cerebral blood supply who would be most likely to suffer stroke. However, the trial was stopped for futility once the two-year results for 194 participants were analysed: surgery plus medical therapy prevented no more strokes than medical therapy alone.

2011   Generally speaking, it is best not to meddle with the cerebral circulation, but in the case of people with arteriovenous malformations in the brain, it may be necessary. Then it becomes a question of whether to lift the cranium and do microsurgery, or to try and ablate the malformation, using stereotactic radiotherapy or by introducing an embolizing device. This systematic review shows a diminishing case fatality with time but a wide spread of results in individual trials. Overall, the rates of permanent neurological deficit or death vary little between the three modes of treatment, at 5-8%.

2022   Giving a “Grand Rounds” talk at the department of Internal Medicine at Yale the other week, I used several video clips of patients speaking and was reminded of how powerful a tool this can be. In fact I’d go so far as to say that no talk about anything connected with what patients think, need, or experience should ever be given without a few clips chosen from the endlessly rich collection on www.healthtalkonline.org. It’s the product of more than ten years of careful, open interviewing and thematic selection: it’s there to show the full range of patient experience, not to illustrate anyone’s public polemic. But here is an opinion piece from the USA (which has no such collection) suggesting patient videos should be used to give emotive weight to public health messages, such as MMR vaccination. I do hope this never happens. In the adversarial culture of American medicine and politics it seems almost inevitable that it would lead to highly publicised “clip wars.” That is exactly what the late, great Ann McPherson strove to avoid when she set up her visionary DIPEx project in 2000: she wanted all patients to have a voice, not to be set shouting at each other.

NEJM  10 Nov 2011  Vol 365
1763   Have you ever eaten fenugreek sprouts in Germany? If you have, it is possible that memory may have blotted out the experience; or else that some soup, modge, stew, or salad that you politely made your way through might have contained the sprouts without your being aware of the fact. These are ever-present dangers with German cuisine; moreover, it seems that even the Germans themselves can suffer from sprout amnesia. During the epidemic of Shiga toxin-producing E coli that affected Germany in May this year, sufferers were naturally urged to try and recollect the foods that they had eaten prior to becoming ill: 88% remembered eating cucumber and 25% remembered eating fenugreek sprouts. But at the end of one of the most intensive public health investigations ever undertaken, the culprit in every case was found to be fenugreek seeds. Most unfortunate sufferers had chosen to eat at a restaurant where no fewer than half the dishes were garnished with fenugreek. Don’t believe studies that depend on people’s recollected food intake.

1771    The brief German epidemic affected 3816 people, of whom 54 died. The epicentre was Hamburg, with two other small restaurant-based clusters to the south. This paper will become an instant classic of the epidemiological literature: a John Snow-like E coli map of Germany combined with modern bacterial genomics and an account of the clinical course of the worst affected patients. The accompanying editorial tells the story of how the epidemic may have begun with contaminated fenugreek seed from Egypt in 2009: fascinating and well worth trying to access.

Lancet  12 Nov 2011  Vol 378
1699   A cluster randomised trial from Australia looks at some of the components that might constitute good acute stroke care. Unfortunately it combines three interventions – swallowing assessment, fever control, and blood sugar control – which may or may not be of equal importance. Deliver all three interventions and you can achieve a 15.7% (95% CI 5.8-25.4) reduction in death and dependency at 90 days. The editorial describes this as “dramatic” but goes on to wonder which of these measures is really important: for example, a swallowing assessment before giving oral food or drugs is generally accepted as essential, but was achieved at less than the normal UK level even in the intervention group. You may wonder if giving paracetamol for fever, and fluids for mildly elevated blood glucose, really add all that much. And perhaps the greatest improvement in results was due to none of these but simply the closer coordination of care in the intervention group.

1707   It’s good to see the Oxford clinical trials support unit putting its efforts to good use in this meta-analysis of individual patient data from 10 801women who received radiotherapy following breast conserving surgery for cancer. I can hardly do better than to quote the conclusion of the abstract: “After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.” That really is good news. The CTSU should focus its efforts on studies of this kind rather than attempts to promote HDL-C-raising drugs for pharmaceutical companies.

1727   It’s interesting to compare and contrast the two Seminar pieces this week – the first on non-small-cell lung cancer and the second on small-cell lung cancer. The latter condition – called “oat cell cancer” when I first walked the wards, scarcely pausing at the bed of an emaciated old man with clubbed brown fingers – is still generally lethal, and all the seminar can do is describe regimens of chemotherapy which might mean a life expectancy of 6 rather than 3 months. With non-small-cell cancer, though, we are dealing with range of different tumours with varying genetic characteristics, which is why I get impatient with the term. Fortunately it seems likely that with better characterisation will come better treatment, which may even be curative. Horton’s question “why has the gene revolution failed so spectacularly to deliver anything tangible for patients?” may apply to most population-wide SNP hunting but doesn’t really apply to cancer genomics, where scientists are looking at the genes of cancer cells to devise new ways of killing them. In fact this area may be seeing the growth of a new kind of open drug development not seen since the days of penicillin and Florey, Chain and Heatley: http://www.ted.com/talks/jay_bradner_open_source_cancer_research.html

BMJ  12 Nov 2011  Vol 343
The formidable list of authors at the head of this systematic review of referral to exercise programmes in primary care includes four professors with “exercise” in their titles, so I was worried that this might be the equivalent of setting on the Vatican to do a systematic review of the benefits of regular confession. But no: it makes it all the more startling that they are forced to conclude that “Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.” That’s not to decry the value of exercise itself, of course: it just needs to be part of a daily routine together with working, eating, drinking and sleeping.

Another first-rate qualitative study here in the BMJ research pages: interviews with 28 men from the West Midlands who had undergone surgery for colorectal cancer. Most of them were experiencing erectile dysfunction as a result, though none of them had been warned to expect it. This reminds me of Jack Wennberg’s pioneering work in the USA in the 1980s, when he was examining informed patient choice in surgery for benign prostatic enlargement. Some men feel suicidal at losing sexual function, most find it traumatic, whereas for a few it matters little. This single study, consisting of simply talking to patients, is all that should be needed to show the urgent need for proper sexual advice to patients about to undergo colorectal cancer surgery. I hope that in a few years it will be seen as a key example of how studying the patient experience can be used to improve patient care.

Plant of the Week: Prunus subhirtella var. Autumnalis by Eric Larson 2008

This time of year it’s hard to find things blooming in the landscape. Difficult but not impossible. For instance, Dandelions (which have been promoted on this page in years past), a few struggling Cosmos, a few Roses, Chrysanthemums of course, some species and hybrid crosses of Witch-hazel, the fabulous Camellias, Winter Jasmine and others. If you have something blooming or reblooming in your landscape, email me back and let’s talk about it.

Autumn –blooming Higan Cherry is a variety, or naturally occurring variation of the species, kind of like a redhead in human terms. The species is one of about four hundred thirty within the genus, and they are naturally occurring throughout the temperate regions of the northern hemisphere. The genus name derives from the Latin name for the Plum Tree. I could not find an etymological source or meaning for “subhirtella.” So this is another reason for a return e-mail from an astute reader. The genus has traditionally been included in the Rose family, Rosaceae as a sub-family, Prunoideae. Some botanists have carved out a separate family, Prunaceae (or Amygdalaceae). The genus includes Plums, Apricots, Peaches, edible and flowering Cherries and Almonds. The Higan Cherry is native to Japan. The Weeping Cherries are usually the weeping form of the Higan Cherry grafted onto another rootstock.

The species grows to a height of about forty feet tall, with a spread of about half or two-thirds of that. While the weeping form tends to not get that tall, the Autumn-blooming Cherry will approach that. The Autumn-blooming Higan Cherry will bloom sporadically in fall after leafdrop, especially with the warm weather we’ve been having. Then in spring before the leaves emerge, it will bloom more fully, providing two seasons of bloom, which is rare for small flowering trees. The buds are deep pink, giving way to soft pink and gradually aging to an almost pure white. Autumnalis flowers are semi-double (10 petals) and about one-half to two-thirds of an inch across. The subtle sporadic pink flowers of Autumn-blooming Higan Cherry would go nicely in an enclosed courtyard, against an evergreen background or perhaps beside a brick or dark-colored stone wall. The tree likes full sun to partial shade, a well-drained average garden soil and will require little or no care as regards pruning or pest control.

Note by RL: A wonderful tree but liable to bacterial blight in damp England, like all Prunus spp.

JAMA  2 Nov 2011  Vol 306
1874   The older you get, the more likely you are to have a haematological malignancy, and the less likely you are to be able to stand up to the rigours of myeloablative therapy followed by allogeneic haematopoietic cell transplantation, which can offer a cure in younger patients. You might think that total myeloablation was essential to the success of donor bone marrow grafting, but in fact it is not: some at least of the effect is mediated by a graft versus host reaction. So it might be possible to use half-dose radio-ablation and still get some survival benefit from cell transplantation: and this is confirmed in a multinational trial which enrolled 372 patients aged 60 to 75. Their five-year survival was 35%. Mind you, the treatment is not particularly pleasant, and the frequency with which graft-v-host reactions occur means that many patients have to take long-term steroids with a range of adverse effects.

1884    Here is an analysis of breast cancer risk in relation to alcohol intake from the 106,000 women in the US Nurses’ Health Study. Between 1980 and 2008, their alcohol consumption was recorded on 8 occasions, and there were 7690 incident cases of breast cancer. Sadly, the analysis shows that even slight consumption raises the risk of invasive breast cancer: in fact alcohol seems to be carcinogenic to the female breast in a dose-related manner. Gentlemen sharing a bottle with ladies should see to it that they have most of it.

NEJM  3 Nov 2011  Vol 365
1663   Those of you who have read Atul Gawande’s book Better (and that should be all of you) will remember a chapter on cystic fibrosis which describes how truly aggressive, insistent treatment can improve outcomes. To me, this is not a welcome message. It means that patients have to live lives dominated by their illness; and as someone said when Leonard Cheshire was awarded the Victoria Cross for repeatedly flying low and fast through German air defences as a bombing pathfinder, you can’t operationalise something that deserves the highest honour for valour. We need a routine treatment for cystic fibrosis that will improve outcomes for everyone irrespective of exceptional effort. Ivacaftor may or may not be this treatment: but it certainly marks a new step in the search for one. It pains me to admit it, but this is an actual success for genomics-led, bench-to-bedside pharmacology. The gene for CF was discovered in 1989; the most common mutation is ΔF508-CFTR, but for some reason the pharma boffins have been more successful at targeting a much rarer defect in G551D-CFTR, present in fewer than 10% of people with CF. For this subset, ivacaftor is strikingly successful in improving lung function over 48 weeks. It also reduces sweat sodium and prevents infective exacerbations. If such promise can be maintained in the long term, through the use of this and other targeted drugs, CF may become compatible with near normal life expectancy and even with leading a nearly normal life. 

1673   In this next paper, new ground-breaking science is used to combat the effects of existing ground-breaking science. We saw from the first JAMA paper this week that graft versus host disease (GVHD) is an almost inevitable problem when using allogeneic cell transplants. But what if you could simply kill off the allogeneic cells once they have done their job and start becoming a nuisance? A trial in five patients of a cell-suicide system to achieve this was a complete success. It’s a pretty amazing story: you take the cells that are going to cure the patient, in this case genetically modified T-cells for patients with relapsed acute leukaemia. Spliced into these cells is caspase 9 (iCasp9), which means that they will die as soon as they come into contact with AP1903, an otherwise bioinert small-molecule dimerizing drug. So if the T cells start replicating and causing GVHD, you simply inject some AP1903 into the patient and the T cells vanish. It seems to be as simple as that.

1702   I try to provoke comment in these reviews, but I seldom get any unless I attack people for pronouncing Clostridium difficile in the French manner. I won’t go there this time: the Consortium de Recherche sur le Clostridium difficile was set up by Canadians who prefer to speak French rather than English. Let them be as difficile as they please: one cannot reason with such people. In this very well-conducted study they determine the host and pathogen factors for colonization and infection in acute hospitals. The usual suspects are there amongst the host factors: age, antibiotics, and acid suppressing medication prior to admission. The chief pathogenic culprit in hospital infection is the strain of C diff known NAP1.

1713   Do you understand ulcerative colitis? If so, please step up and share your knowledge with us, since this comprehensive review only serves to show that nobody else does. I remember being puzzled as a medical student nearly 40 years ago that nobody seemed to know what causes so dramatic a condition, and we still seem to be at much the same stage of vague theorizing about abnormal reactions to the gut flora, coupled with auto-antibody formation in the form of circulating IgG1 antibodies against a colonic epithelial antigen that is shared with the skin, eye, joints, and biliary epithelium. As for treatment, surgery has improved a bit in the last 35 years, and physicians now have infliximab to use as a nearly last resort drug.

Lancet  5 Nov 2011  Vol 378
1627    This study comes from the intensive neonatal care units of Germany, where it has become common practice to slip a thin tube down the trachea and squirt a bit of surfactant into the airways of babies requiring continuous positive pressure ventilation, to prevent worsening respiratory distress syndrome and the need for intubation. Until now, nobody had put this method to the test of a randomised controlled trial. Now they have, and it works.

1635   And now – amazingly for The Lancet – another useful randomised trial addressing a useful clinical question: in removing a cutaneous melanoma more than 2mm thick, should the excision margin be 2cm or 4cm? The answer is that it does not matter.

BMJ  5 Nov 2011  Vol 343
I was a skinny kid because my parents were poor and I walked everywhere and didn’t get a lot to eat. Nowadays if your parents are poor you are more likely to grow up obese. Despite a huge amount of confident political assertion and a certain amount of research, we don’t fully understand the causes of childhood obesity and we certainly don’t know how to combat it. The diligent Swiss decided to have a go in two high-immigrant city school catchments, putting in four 45 minute exercise sessions every week and lots of teaching about healthy eating, sleep, and exercise. “Regardless of consent, participation in the intervention was mandatory for all children.” Gosh. Those who underwent the compulsory intervention got fitter, but at the end of the study their BMIs were no different from the control group.

Do mobile phones cause brain tumours? No, fortunately. This study examines the entire population of Denmark and finds absolutely no correlation between mobile phone subscription length and the incidence of brain tumours.

When the first successful trials of fixed-dose oral anticoagulants appeared some years ago, I suggested that their manufacturers should fix their prices so that they exactly equalled the current cost of warfarin and its complex system of INR monitoring. They did nothing of the kind, of course. So for the next fifteen years at least we will have a two-tier anticoagulation system: a lucky few will be allowed (or be able to afford) the new drugs and the rest will continue to queue up for regular blood tests. The quantitative harm-benefit part of this paper shows that the direct thrombin inhibitor dabigatran etexilate is clinically superior to warfarin; but the economic analysis suggests that for all but the highest risk patients, warfarin remains more cost-effective.

Ann Intern Med  1 Nov 2011  Vol 155
569    In the far-gone hippie era, there was a vogue for all things Indian: meditation, ragas, curry, and yoga. Of these, yoga was the most difficult and the first to fall out of fashion. But we were left with a vague feeling that if one persevered in twisting one’s legs in odd ways, one would achieve some kind of better karma and perhaps even better health. This British trial looks at the effect of a 12-week course of yoga on low back pain over a period of 12 months. Alas, it had no benefit, and the commonest adverse effect was worse back pain. Stick with curry and ragas, say I.

Plant of the Week: Araucaria araucana

Inside Yale’s Peabody Museum, a couple of hundred yards from where we live, there is a splendid collection of dinosaurs in a vast hall surrounded by a mural of life in the Cretaceous period. Repulsive huge reptiles stomp about a landscape dominated by volcanoes and forests of palm, gingko and monkey puzzle trees: all very thrilling. In the last year, a Cretaceous garden has been planted outside the museum, watched over by a life size bronze Torosaurus on a rough block of pink granite. Around him they have planted various trees of similar antiquity. There is also grass, which I first thought was a mistake, but it seems that grasses began to flourish in the age of the dinosaurs.

A week ago we had an unseasonal fall of snow, and the snarling Torosaur looked very impressive, with white drifts on his back and head, and a little gingko tree with its leaves turning golden beside him in the snow. Also standing by imperturbably was a tiny monkey puzzle tree, destined in time to become taller by far than the museum itself, let alone the dinosaur.

Do not, whatever you do, buy one of these baby araucarias in a nursery pot and stick it a garden bed. Probably the only circumstance in which the purchase of an araucaria can be deemed wise is if you own a large tract of land in Western Scotland which you intend to bequeath to your grandchildren. In that case, plant an araucaria forest with a ratio of six female trees to every male (but beware: they sometimes change sex in mid-life). In about 30-40 years they will bear copious crops of cones which will fall to the ground, yielding huge numbers of edible nuts. You will not live to see the day, but you will have started the Scottish nut industry, and history will record your name as a benefactor of mankind. Scottish history will, anyway.

I first read the story of how the monkey puzzle tree arrived in Britain in a book about Kew Gardens, which is currently gathering dust three thousand miles away. From memory, it runs thus. Captain George Vancouver set out with two ships to explore the west coast of northernmost America in 1791. He had mixed success since various Spaniards and Frenchmen had just beaten him to it, and on his way back in 1795 he took supplies in Chile, where he was entertained by the liberator Bernardo O’Higgins. This bit cannot be true, since Bernardo was aged 17 at this date, and had not liberated anywhere, though he did indeed go on to do both Chile and Peru. The gentleman in question must have been Bernardo’s father, Ambrosio Bernardo O’Higgins, born Ambrose Bernard O’Higgins in Sligo, but by this time ruling Chile on behalf of the Spanish monarch.

Feasting with O’Higgins, Vancouver was impressed with some strange nuts served near the end of the meal, and slipped a few into his breeches pocket. When he arrived back in London, he gave some to Joseph Banks at Kew Gardens. Banks carefully tried to germinate them under glass at Kew and when a young tree sprang from one of them, he tended it in the garden under a specially constructed glass pyramid. Nobody had seen anything like it. A few cuttings were taken from it and sold to the nobility for extravagant prices. But then disaster struck: high winds and snow destroyed the glass pyramid and the infant tree was left exposed to the British winter. Nobody then knew that this was a tree from the mountains of Chile and completely hardy to snow, wind and frost. It simply carried on growing, as its forebears had for 250 million years. It became one of the chief attractions of the garden, summer and winter.

In early life, the tree has a certain appeal, with its stiff branches covered in tough dark green scaly leaves. But in mere adolescence, it starts shedding leaves from the lower branches, which then stick out in ugly bareness and eventually drop off. As it moves towards adulthood, which can last 1,000 years, it becomes distinctly ugly, with a telegraph pole trunk reaching 30+m into the air, knobbed with branch scars and topped with a scrawny canopy of miscellaneous horizontal branches. Definitely a tree for the Scottish nut industry only.

JAMA  26 Oct 2011  Vol 306
1775    There is now pretty clear evidence that CT scanning to detect lung cancer in heavy smokers can save lives. This Dutch study shows that the same scans can also detect chronic obstructive pulmonary disease in about 38% of the smokers they recruited. In this population the sensitivity of CT was 61% as compared with a “gold standard” of pulmonary function testing. This is not very good: but what does it matter? There is no useful intervention for COPD except giving up smoking, which is what all these people either have done already or need to do anyway.

1794    In the USA as in the UK, hospital readmission has come under intense scrutiny as an avoidable burden on the health system. But is it really? It is just what happens when you combine an ageing population with deeply entrenched patterns of care, and to change these would require root and branch reform of the whole system. Certainly all the evidence I have seen suggests that it is a lousy quality marker for hospitals, and that parachuting in complex interventions may achieve some temporary local success, but that these are rarely generalizable across all conditions and all settings. The problems in the USA are magnified by horrific social inequalities, disorganized primary care, and perverse incentives within an endlessly complex payment system. Be sure that in America the insurance companies and provider organizations will be one step ahead of any clumsy attempts by federal government to rein in spending. And be sure that we have the same thing coming to us in the UK if we allow the NHS to disintegrate further into a chaos of competing semi-autonomous purchasers and providers, gaming with government over an endless series of penalties and incentives.

NEJM  27 Oct 2011  Vol 365
1567   Here’s the second study this week to use cancer-screening chest CT to study COPD. But the Canadian-US investigators go a good deal further – in fact all the way down the small airways – to study the pathogenesis of emphysema at each stage of COPD progression. In a few cases they even have lung tissue samples from patients subsequently operated on for cancer. It makes you wonder how smokers manage to breathe at all. Long before the appearance of radiological emphysema, there is almost total destruction of the small airways.

1576   The same human papillomavirus subtypes (mostly 16 and 18) that produce dysplasia and cancer of the cervix are even more strongly associated with similar changes in the anal area of people who have receptive anal sex. This study recruited 602 men who have sex with men to determine whether HPV vaccine can protect against anal HPV infection and anal intraepithelial dysplasia. The study was only just sufficiently powered to detect a protective effect against dysplasia in the intention-to-treat analysis, but in the per-protocol analysis it had a convincing effect, and is likely to be a useful measure against the rising incidence of anal cancer in men and women.

1586   Briakinumab is a monoclonal antibody targeted at the p40 molecule which is overexpressed in psoriasis. Abbott Laboratories ran a year-long trial which proves that this is a very effective treatment for moderate-to-severe psoriasis compared with methotrexate, producing 75% clearance in 80% of patients on weekly briakinumab, compared with 40% taking weekly methotrexate. It could be a great drug, but might also be a dangerous one: there are hints that it might carry a risk of major infection and of cancer, but we won’t know how big the risk is until longer studies have been done.

1597   Life is incredibly unfair to fat people. It seems that evolution has programmed humans to hang on to every scrap of fat they lay down, as insurance against lean times. So if an obese person loses weight, every appetite hormone in the body and brain strives to restore it, and keeps striving for at least a year. This study measured differences from baseline in the mean levels of leptin, peptide YY, cholecystokinin, insulin, ghrelin, gastric inhibitory polypeptide, and pancreatic polypeptide, as well as hunger levels, twelve months after a weight loss programme in adults with diabetes. They were all still significantly different from baseline. And I suspect that the more times people go through the cycle of weight loss and regain, the more the body interprets this in terms of a starvation/plenty cycle, and produces still more of the hormones and hunger signals that drive us lay down fat.

Lancet  29 Oct 2011  Vol 378
1538   Following the example of a friend, I have taken to reading Richard Horton’s weekly Offline column, to find out what he is doing instead of editing The Lancet. It can be quite odd and disturbing at times, but this week he reports an amazing experience: he has become aware of the moral grandeur of British general practice. His first Damascus Road moment came at the Royal College of Physicians, where he fell to the ground blinded by the radiance of Iona Heath’s Harveian Oration. Later in the week he heard Clare Gerada calmly rebutting Andrew Lansley in Liverpool, and his conversion was complete. But I don’t think we should count on him turning from persecutor to missionary for primary care just yet. Just let’s rejoice with him that in the worst crisis to face general practice since the founding of the NHS, our College has the best leadership since it came into being.

1547  Dalcetrapib raises HDL-cholesterol by modulating cholesteryl ester transfer protein (CETP) activity. The last drug to do that, torcetrapib, actually increased cardiovascular harms, and was withdrawn in 2006. And despite more than 200 trials, no non-statin HDL-raising drug has ever been shown to have cardiovascular benefit. Still, Hoffmann-La Roche decided to try and prove that their own CETB-modulating  HDL-lowering drug was less likely to kill people than torcetrapib, so it got a team together to demonstrate this using a specially devised form of arterial wall measurement (dal-PLAQUE). Nobody knows what this novel measurement really predicts, but we are told that because dalcetrapib does not change it in 64 subjects over 12 months, it is likely to be safe. So they are testing a drug which is intended to alter a surrogate marker in millions of people at increased risk of cardiovascular events, and the best evidence they can produce is its lack of effect on another, specially devised, surrogate marker in a tiny sample of subjects. What are we meant to think about a journal that gives space to this stuff?

BMJ  29 Oct 2011  Vol 343
I’ve always felt a bit uneasy about using prothrombotic drugs like tranexamic acid, but it does seem to be useful in some situations of excess bleeding from the uterus or bladder. I’d be particularly uncomfortable about using it in anyone at added risk of thromboembolism, for example due to cancer or major surgery. But a team of Italian investigators went ahead and used low-dose tranexamic acid during radical prostatectomy for cancer, and so reduced bleeding and the need for blood transfusion. Moreover the cheap old drug had no effect on VTE events over the ensuing months.

Now to California, for a large cohort study of women taking antihypertensive drugs during the first trimester of pregnancy. Their overall risk of having a baby with a significant malformation, especially of the cardiovascular system, is increased by about 50%. The study shows that this increase is unlikely to be any different in women taking ACE inhibitors than in women with hypertension in pregnancy generally, whether taking drugs or not.

A little piece called Good news about the ageing brain caught my attention, for some reason. The good news is that oldies can often learn to perform electronic operations, albeit more slowly than the young. I have accordingly signed on to Twittter, as RichardLehman1, though I have no idea what to do next. Somebody please help me while I have a nice mug of cocoa. 

Another advantage of old age is that you can take a synoptic view of human folly while basking in a sense of your own wisdom. The phrase “boring old fart” sums it up perfectly. Nothing in medicine strikes me as more foolish than the amount of money, effort and guile which we allow to be spent on distorting and concealing the evidence base of medicine, while others spend less money but even more effort on trying to assess bias in randomized trials. Here the great notables of the Cochrane Collaboration join to lay out an instrument for getting tough on this form of crime. But what we need is an instrument to get tough on the causes of this crime: and I think we may have just devised one here at Yale. Full disclosure of all human trial data is the only path to a proper science of evidence-based medicine. It is also an ethical imperative.

Fungus of the Week: Lactarius volemus

This is a handsome woodland fungus of stately bearing with a felty cap of a colour between brick and burgundy red. As soon as you pick it, it will start to ooze milky sap from its pale yellow gills. If you put a drop on your tongue, nothing happens: it will not fill your mouth with a burning acrid taste like many other Lactarius species. Later on, the gills will develop a fishy smell. In Roger Phillips’ Mushrooms and Other Fungi of North America he describes it as “Edible – good.” The same description may be found on his website.

His original book of British fungus photographs reached its thirtieth anniversary last week, and the friend who imparted this information also tells me that it has sold a million copies. Like everything he has produced before or since, it is an indispensable guide, giving you everything you need to see and know. Mind you, my own comment on this fungus would read more like “Edible: like cardboard. May be used to absorb bacon fat and should be eaten (if at all) fried with bacon and a scrap of onion.” The same also applies to the ill-named Lactarius deliciosus.

Roger Phillips is a life-enhancing person who has spent his whole life taking photographs of desirable plants and interesting fungi all over the world, and sharing them with us in beautiful, affordable, well-annotated books. I wish him every joy, and I cannot think of any greater than continuing to do the same for as long as possible.

JAMA  19 Oct 2011  Vol 306
There are definite green shoots of recovery in this week’s JAMA. Howard Bauchner hasn’t yet made the sweeping changes he’s promised, but there’s a nice mix of papers and the poetry remains as thrillingly bad as ever.

1659   A few weeks ago, The Lancet ran a couple of papers about desperate remedies for Shiga-toxin producing E coli, indicating that plasma exchange might be a life saving treatment. Here is the equivalent observational study for severe acute respiratory distress syndrome caused by H1N1 influenza. Patients whose blood gas levels could not be maintained in a local intensive care unit were either kept there or sent to one of four hospitals in the UK which offer extracorporeal membrane oxygenation (ECMO). This was not randomization, and only afterwards were their characteristics matched using software called GenMatch. But for all the obvious limitations of this study, the result is pretty convincing: similar patients stood twice the chance of survival if they received ECMO.

1669   I first started following the epidemiology of heart failure in the mid-1990s, and kept coming across the name Harlan Krumholz on all the best papers from the USA. And still they keep coming: here is a painstaking study of the patterns of heart failure mortality and hospital admission in all 50 states of the USA, plus DC and Puerto Rico, between 1998 and 2008. Deaths have hardly declined but hospital admission rates are down by 29%. The work that went into this classic analysis of Medicare data by Jersey Chen is mind-boggling. Now I myself am working in Harlan’s unit, so I have the privilege of attending their fortnightly publications-in-progress meetings; and I can assure you that this river of good studies is not going to dry up any time soon.

1679    And next a nice little piece of Canadian detective work. Manufacturers of haemodialysis membranes had taken to sterilizing them using electron beam radiation. Coincidentally, a few haemodialysis patients had their blood counts done post dialysis and were found to be short on platelets. This isn’t all that unusual, but gradually a pattern began to emerge. Patients dialyzed on the new machines in British Columbia, with electron-beam sterilised membranes, were getting thrombocytopenia, whereas those on older machines weren’t. Was this a specific manufacturer problem or did it apply to membranes supplied by a different manufacturer, also using electron-beam sterilization, in Alberta? Indeed it did. I rest my case, m’lud: the electron beam is guilty as charged. And the charge is −1.602×10−19 coulomb per electron.

1688    Hospital readmission is a complex phenomenon, governed by a wide range of factors, as every GP knows. The nature of the disease, the availability of supportive care in the community, social circumstances, patient anxiety, adequacy of follow-up, compliance with therapy etc etc. – how can you put all these and a hundred more into a risk prediction model? Very inadequately, is the conclusion of this systematic review. Still, that’s not going to stop the UK government using readmission data as a stick to beat GPs; or is it hospitals? Or both, perhaps. Someone should make the Coalition cabinet sit down for a day listening to the limitations of multiple regression analysis. If nothing else, it would be a dreadful punishment for their crimes.

NEJM  20 Oct 2011  Vol 365
Almost the whole of this issue of the New England Journal is free, because it is about tuberculosis in people with HIV infection. Try to put yourself in the position of a health worker trying to save the lives of hundreds of such patients in the conditions of an under-resourced clinic in Cambodia or India or Botswana. You have no diagnostic facilities to speak of, though perhaps you can do chest X-rays and even CD4+T- cell counts if a generous donor has been your way. Each of these patients will need three antiretroviral drugs, three anti-TB drugs and probably antibiotic and antifungal cover too. Depending on what you do, the patient may make a full recovery or else die of galloping TB if you give the antiretroviral therapy (ART) before the anti-TB drugs, or AIDS if you give ART too late, or immune reconstitution inflammatory syndrome (IRIS) if you start treating the TB too early or in the wrong patients.

Three trials here reach similar conclusions. Treat the TB first for two weeks, then start ART. Don’t worry too much about IRIS except in people with generalised TB or TB meningitis.
http://www.nejm.org/doi/full/10.1056/NEJMoa1013607
http://www.nejm.org/doi/full/10.1056/NEJMoa1014181
http://www.nejm.org/doi/full/10.1056/NEJMe1109546

1520   Panretinal Photocoagulation for Proliferative Diabetic Retinopathy is a common treatment which we leave to clever ophthalmologists with clever machinery. It is amazingly successful for the most part, and it works by burning away hypoxic pigment cells in the peripheral retina which soak up oxygen and produce vascular endothelial growth factor, both of which are very bad things for the viable cells in the macula. Early treatment has been shown to give the best results, though the absolute benefit is small. Read all about it here.

1541    The film Contagion gets a four-star rating in this week’s BMJ, confirming the views of my wife and a friend who came away impressed and scared. Given that influenza viruses can mutate and mingle so dangerously, how can we ensure the survival of civilization as we know it? Step forward Corti et al. who screened 104,000 plasma cells from donors who had antibodies to three diverse influenza types, and discovered just four cells which carried a universal anti-influenza antibody. They then performed an exact characterization of the antibody. So the Holy Grail has been found! Now we need to fashion the Holy Spear which will defeat the hordes of Satan, in the shape of a universal influenza vaccine.

Lancet  22 Oct 2011  Vol 378
1461   There’s nothing that Richard Horton likes better than to sound off about issues of global health, and the best thing about The Lancet under his editorship has been the endless stream of papers delineating various aspects of global epidemiology. This latest effort is concerned with breast and cervical cancer in 187 countries between 1980 and 2010. Skim through the text and pore over the multi-coloured world maps and incidence charts if you have a subscription to this strange publication. How much more useful these prodigious compilations of data would be if they were posted free on www.gapminder.org  – the most interesting website in the world if you are interested in global issues.

1485    But of course The Lancet is also the standard bearer of rigorous British standards of medical research and publishing. Here is a trial paid for by Weight Watchers International. Participants with BMI between 25 and 35 were randomised to Weight Watchers or standard care. The overall dropout rate was around 43%. According to Figure 2, those completing the WW programme ended up with a mean weight of 80kg as compared with 84kg in the standard care group, which is the biggest difference the data can bear. This figure is a classic example of how to make small differences look big by chopping off the bottom end of a scale. Two different intention-to-treat analyses show that WW was about 2.3-2.8kg superior at 12 months. So those of us who advise our patients to try Weight Watchers are vindicated; they may lose an extra 5-7 pounds in a year, provided they are not seriously obese to start with. The authors naturally conclude that with such an effective intervention already available on everyone’s doorstep, there is no need for health systems to indulge in expensive provision of their own. We have no way of watching the weight of reprints that The Lancet now sells to Weight Watchers.

BMJ  22 Oct 2011  Vol 343
How can you tell when someone is genuinely close to suicide? This is not an easy subject to investigate and I was impressed by this qualitative study of those close to 14 people aged between 18 and 34 who had killed themselves. There is way to summarise the findings of as complex a study as this, but I agree wholeheartedly with the Conclusion: “Efforts to strengthen the capacity of lay people to play a role in preventing suicide are urgently needed and should be informed by a thorough understanding of these difficulties. They should highlight the ambiguous nature of
warning signs and should focus on helping people to acknowledge and
overcome their fears about intervening.”

Polycystic ovary syndrome is an endocrine disorder with ill-determined boundaries and uncertain treatment, but the label definitely means something in terms of fertility, diabetes risk, and birth outcomes. This Swedish cohort study sheds some light on the obstetric risks, by comparing outcomes in 3787 births in women with the label of PCOS with over a million other births. PCOS confers a 25-69% added risk of pre-eclampsia, and more than doubles the risk of gestational diabetes and very premature birth. Babies born to such mothers tend to be large-for-dates, to have lower Apgar scores, and are more liable to meconium aspiration.

“Estimating treatment effects for individual patients based on the results of randomised clinical trials” – how about that for a bold title? It’s just what we’d like to do for everybody all the time. But when we come to look at the randomised trials, for example of glucose lowering in diabetes, we find that the trials of the last 40 years tell us exactly nothing useful about the treatment effects for individual patients using any agent. This paper is an academic exercise based on the JUPITER trial of rosuvastatin. It introduces the new concept of NWT – number willing to treat. I in turn suggest a new measurement for articles of this kind – the NWR – number willing to read. I am afraid that I am not of this number. It is true that we can extract some extra information for clinical decision-making by better modelling using existing data. But until human experimentation using drugs and devices is taken entirely out of the hands of people with an interest in marketing them, and is designed by consensus to reach end-points that matter to patients, we shall merely be trying to produce better filters for muddied water which mostly remains undrinkable.

“Non-responding” presumed lower respiratory tract infection in primary care is the stuff of general practice: no winter week will pass without us seeing a few cases. This article is about a 49 year old lady who is not satisfied by her improvement after a week’s course of antibiotics. It is written by a clinical research fellow and a hospital chest physician: it is very unlikely that they ever see such ladies, except socially. But they trundle through the pros and cons of various investigations and then conclude that the general practitioner may wish to point out that acute cough can take two or three weeks to resolve and may not need a further antibiotic. Gosh. It’s uncanny how these people have learnt our skills.

Ann Intern Med  18 Oct 2011  Vol 155
481    In the USA, mammography is a belief system and is to be approached with the respect which polite people accord to the irrational. If people here are ever going to be weaned from the belief that it is in their interests to have their breasts squashed and irradiated every year, and biopsied for lesions that may never do anything, then it must be done very slowly. This paper makes a beginning by showing that outcomes are just the same if you do mammography every two years instead of every year. The same authors proceed to show that digital image capture has no clear advantage over conventional breast radiology.

520   Hospital readmission is a complex phenomenon, governed by a wide range of factors, as every GP knows. The nature of the disease, the availability of supportive care in the community, social circumstances, patient anxiety, adequacy of follow-up, compliance with therapy etc etc. Oops, am I repeating myself? We’ve already read about this in JAMA – there it was about risk scores for readmission, here it’s about interventions to reduce 30-day readmission. And would you believe it – if you do a systematic review, none of these interventions can be shown to work consistently. It’s almost as if this is not a simple problem with a simplistic answer.

Plant of the Week: Acer saccharum

This is the Sugar Maple, a great source of income to the peoples of northern North America both from the syrup it produces and from the spectacular beauty of its autumn leaf colour, which fills the guest houses of Vermont and Maine and Canada with troops of “leaf-peepers” at this time of the year.

Syrup tapping is a spring activity, as the sap rises in the trees when the sun gets stronger. Maple syrup is still collected entirely in the wild from vessels placed under pipes hammered into this species of maple and the closely related Black Maple, A nigrum. Vermonters rise at frosty dawn for several weeks of the early year to identify these trees and collect their sap as it is squeezed out by the alternate action of frost and sun. They sell postcards depicting visitors who knock their tapping pipes into telegraph poles.

The Sugar Maple also has hard wood which is valuable as timber. Do not confuse it with Acer saccharinum, the White Maple, which has brittle, useless wood and no sugar. It is only useful for bringing down power cables in windy weather, and lifting up paving slabs with its shallow roots.

JAMA   12 Oct 2011  Vol 306
1549    It has been a bad week for vitamin supplements. Worst hit, as usual, has been vitamin E. The SELECT trial began collecting 35 000+ healthy men with normal feeling prostates back in 2001 and randomised them to get a selenium supplement, a vitamin E supplement, both, or placebo. Those given vitamin E had a “significantly increased” risk of prostate cancer –by a factor of 1.6 per thousand person years. Even selenium seems to do a tiny bit more harm than good in this respect. Once again a properly conducted large RCT puts to bed a mass of anecdote, observational “evidence,” bad little studies, and health supplement advertising.

1566   I’ve never quite understood how α-tocopherol managed to get the status of a vitamin with its own capital letter, whereas the truly vital amine folic acid is plonked somewhere with the other B vitamins and often forgotten about. Since the 1970s, we have become keenly aware of its role in early fetal neurodevelopment, especially the prevention of neural tube defects. This prospective observational study from Norway looks at nearly 40,000 children born to mothers who did or did not take folic acid supplements from 4 weeks before conception to 8 weeks after. Severe language delay at 3 years was twice as common in those who did not. The case for folic acid fortification of bread flour grows ever stronger.

1582    But that would be of little use to the one in a hundred mothers who has coeliac disease. I don’t know if anyone has studied neurodevelopmental outcomes in children born to mothers who have subsequently been diagnosed with this common and variable condition. In this clinical review and case discussion, it is claimed that its prevalence has been steadily rising over the last 50 years. This is anything but the case: its estimated prevalence used to be one in 2-10,000; then along came serological testing in the 1990s, and it shot up to 1 in 100 and has stayed there since. It is also described as a disease which shortens life and causes osteoporosis: but again, this only applies to classical grossly symptomatic CD. Taking in the whole spectrum of antibody positive disease, there is little evidence of harm to asymptomatic individuals. But it is still worth testing for in everyone with recurrent anaemia and/or tiredness-all-the-time: some people’s lives are changed by treatment. Others just find it a bore and revert to eating gluten.

1593   Most pharmaceutical and medical device companies conduct human experiments (clinical trials) and then fail to publish the results of some of them at all, or publish them selectively. Through widespread ignorance, and occasional collusion, we have put up with this ethically outrageous situation for decades. “Evidence-based medicine” is often missing half the evidence; patients who gave consent to risk harm so that others might benefit are cheated. There have been occasional calls for open access to all trial data from industry but legislators and regulatory bodies have paid little attention, and until now nobody has come up with a working model for individual patient data to be analysed in a way that guarantees integrity and independence. But in the last 4 months, Harlan Krumholz at Yale has not only come up with the model but has also persuaded the largest medical device company, Medtronic, to support and fund two totally independent analyses of its data relating to a controversial bone product. I can’t believe my luck in being involved with this benchmark project, which is outlined here by its originator and a close colleague. If any company present knoweth of any just cause or impediment why its human trial data should not be disclosed in this way, let it speak now, or forever hold its peace and deliver them up.

NEJM  13 Oct 2011  Vol 365
1376   Barrett’s oesophagus is a classic example of a condition which has been talked up out of all proportion to its significance. It provides a comfortable living for an army of endoscopists and needless anxiety to countless thousands of individuals who live in daily fear of developing a nasty and usually lethal kind of cancer. In fact just 5,000 people a year die of oesophageal cancer in the USA, and the great majority of these have never had Barrett’s oesophagus. It is true that this is six times the figure in 1975, but it is still a tiny risk. Multiply it by 11 and it is still small, and this is the figure arrived at for the added risk from having a diagnosis of Barrett’s in this Danish whole-population database study. It agrees reasonably well with a previous Northern Ireland whole-population study. There is absolutely no evidence that regular upper GI endoscopy makes any difference. The all-cause mortality of people with and without Barrett’s is identical. As I’ve said before, I do wish he had never invented his oesophagus.

1406    Influenza is a diagnosis we seldom make with confidence in children between six months and six years of age. It is usually a mild febrile illness which rarely needs specific treatment. This Finnish trial shows that by giving two shots of an influenza vaccine with oil-and-water adjuvant, you can effectively protect children from a selected range of influenza viruses, as shown by PCR testing. Following each dose, there is a 60+% chance of a mild febrile illness and a local reaction. So you would have to be jolly worried about your child getting flu to want them to have this vaccine.

1417    In this article about adult primary care following childhood acute lymphoblastic leukaemia, there are two striking figures. One displays survival improvement from 1975 (40ish %) to 2003 (90+%): it’s a great teaching slide to illustrate incremental progress in therapeutics. The red line wiggles slowly upwards as treatment regimens are gradually refined. The other picture is of identical twins, one of who had treatment for ALL as a child. She is unrecognisable as a sister, let alone a twin: several inches shorter, with a moon face and obesity, as lasting legacies of prolonged steroid treatment and an irradiated pituitary. If you have such a survivor in your practice, it’s worth having a look at this piece: though if you carried out every bit of “primary care” that it advises, you might have to cancel the rest of your appointments for a couple of days.

Lancet  15 Oct 2011  Vol 378
1388   Here is a fine example of a genre of Outcomes Research first suggested by Francis Clifton in 1732: the surgical case-series. Two neurosurgeons from Queen Square report on the outcomes of 649 consecutive operations performed for adult epilepsy since 1990. They managed to cure half their patients completely, and most of the rest appear to have benefited. Nice when you can flourish personal results like these in The Lancet, while seeking generalizable lessons on case-selection and surgical technique in adult epilepsy.

1396   As I try to put together a book on Outcomes Research in one of the world’s leading centres of outcomes research, I am naturally keen to learn a bit about the subject. So far I have picked up some of the basics. You need data that are reliable. You need outcomes measures that are well defined and well documented. To link the two you need statisticians who understand the material. If you tried to use the software on your own you would go mad and produce garbage. You might anyway. Often you have to work with data that happen to be there, rather than the data you would like to have. These data are usually complex and so you have to think very hard about what variables matter, how they inter-relate, and what adjustments need to be made. Now this study of preoperative anaemia related to postoperative mortality and morbidity is fairly straightforward. The data come from American College of Surgeons’ National Surgical Quality Improvement Program database, a prospective validated outcomes registry from 211 hospitals worldwide in 2008. Anaemia is defined by haematocrit, which is confusing to UK readers, but is perfectly logical. The post-op outcomes seem reasonably well ascertained. So we can be pretty sure about the bottom line: if you come to non-cardiac surgery with a low haematocrit, you tend to have worse 30 day outcomes. Even mild anaemia is important. But the key clinical questions that arise are not answered in this study: we don’t have any information about the causes or duration of anaemia in this heterogeneous population, nor any information about any therapy given pre-operatively. Like all outcomes research, it suggests that a lot more outcomes research is needed.

BMJ  15 Oct 2011  Vol 343
The BMJ shows admirable impartiality in publishing this study comparing the speeds with which various medical updating sites actually update their material. The BMJ’s own product, Clinical Evidence, is the slowest by a good margin. The paper is written in a translated-from-the-Italian style which is hard to follow; it acknowledges that its methods were essentially bibliometric and did not examine content in detail. So it is quite possible that Dynamed, which dashes to cite everything the moment it appears, may suffer by tending towards the opposite extreme. Given the quality of much of what we call evidence, sometimes slow adoption is a good thing.

Looking at the contributors to diabetes and lipid guidelines in the USA and Canada, the authors of this study find that half of them have conflicts of interest. This is amazing. Where did they find the half without conflicts of interest? This murky topic draws a superb editorial from Edwin Gale and commentary from Fiona Godlee. Something must be done about this: and slowly, I think, there are signs that it is going to be done. But even without conflicts of interest, guidelines will always err towards over-investigation and overtreatment. Try not to use them.

Arch Intern Med  10 Oct 2011  Vol 171
1625    In an already famous contribution to the Less Is More series, a miscellaneous group of authors analyse data from the Iowa Women’s Health Study. In 1986, two-thirds of the cohort (mean age 62) were taking vitamin and/or mineral supplements; by 2004 (mean age 82) this had increased to 85%. There are striking differences between those who did and didn’t in these ill-balanced groups: for example, those not taking supplements did twice as much exercise. So in interpreting the mortality differences cited in this study, bear in mind how much depends on the accuracy of its multivariable adjusted proportional hazards regression models. Still, I am quite content to believe that all this stuff does no properly nourished person any good, and unnecessary iron supplementation almost certainly does harm.

1655   “Two major factors associated with skeletal fracture in older persons are intrinsic bone strength and risk of falling.” Hard to disagree with that. Now there are lots of risk-of-falling scores which we can look up but seldom use. This one requires just a stopwatch and a chair and it is called TUG, which stands for Timed Up and Go. Place your postmenopausal lady of advanced years in a chair and command her to get up and walk 3m and sit down again. This should take less than 10.2 seconds. Measure her hip bone density. Put the TUG score and the BMD together and you have a measure of non-vertebral fracture risk.

Fungus of the Week: Craterellus cornucopioides

Walking up Mount Tom in Rhode Island with my son Tom a week ago, I stopped to tie my bootlace, and he drew my attention to a little cluster of grey tubes emerging from the ground nearby. They were all but hidden in the leaf litter, and only by careful searching did we find a few more of these fabled trompettes des morts scattered in the vicinity. I could have stayed there all day, grubbing about like a hedgehog, but I sensed that this was not the young man’s idea of a good time. We strode to the summit and admired the vistas of New England fall colors. The next day we did Mount Tom in neighbouring Massachussets: a formidable forest climb, but no more trompettes to be found. The next day it was the turn of Mount Tom in Connecticut: fabulous views, but again no trompettes.

Alas, there are only two ways to find this fungus: by happy accident, or by knowing where it grows. To some extent this applies to all fungi, but Craterellus is so well-camouflaged that you have almost to be on all fours to spot it. So far as I know, dogs and pigs have never been trained for this purpose, though these little grey funnels are the nearest thing in taste to an above-ground truffle.

If you have the good fortune to come across some, bake a sea-bass or grill a Dover sole in their honour. Tear the trompettes into small pieces and cook them briefly in melted butter with pieces of shallot. If flavour means more to you than appearance, now add some white wine and reduce briskly: then add thick cream and boil briefly. Pour this sauce on the white fish and sprinkle with finely chopped parsley and a little chive. If appearance is important, you could do the wine and cream reduction separately and add the black trompettes after pouring this white sauce over the fish. But you will pay for your black-on-white showmanship by losing some of the magical intensity of flavour they can impart to the cream: a poor exchange.

JAMA  5 Oct 2011  Vol 306
1461    American medicine is a mass of quirks and contradictions: like medicine anywhere else, but magnified by huge financial forces pulling in different directions. There is a big financial incentive for cardiologists to do percutaneous interventions in elderly patients with stable coronary disease, for example, though the evidence suggests that few of them need it. I don’t know how Medicare handles that dilemma, but it willingly pays for these patients to spend a night in hospital following PCI. And I guess because the hospitals and the cardiologists get paid, nobody complains. But the fact is that most of these patients could perfectly well go home the same day, as confirmed by the small subgroup of patients who actually did in this Medicare patient study. Yet the incentives are all weighted towards them staying in unnecessarily, including the fear of litigation when something goes wrong, as always will happen. So American PCI patients are stuck with a night in hospital, whether they need it or not, and ours are stuck with going home the same day, whether they are fit to or not. I would love to see the day when health services really begin to learn from each other, but until that happens there is only one safe rule: never copy the USA.

1483   Now I shall immediately appear to break that rule by praising this Commentary piece which explains the idea of time-limited trials near the end of life. This has nothing to do with research trials, but rather practical trials of treatment to see if they make dying patients better. The key point is to have an explicit plan for stopping them if they don’t. We all automatically do such trials of treatment in the hope of helping the dying in real life, I hope: the difference here is the clarity with the process is made explicit, and that is something America tends do better than Britain.

NEJM  6 Oct 2011  Vol 365
1273   The main papers in this week’s NEJM give me déjà-vu like I can’t remember. Will there ever be an end to trials of new chemo combinations for breast cancer and new drugs for relapsing multiple sclerosis with tantalizingly small benefits? I suspect that as long as I go on reviewing, I shall have to keep telling you about such things. Incremental advances in combination treatment have led to complete cures for certain types of cancer, but this trial does not get us any nearer to that in HER-2 positive early breast cancer. The title of the editorial, “Steady progress in HER-2 positive breast cancer” belies its message which is that trastuzumab-containing regimens do not improve on existing anthracycline-containing regimens. Anthracyclines can induce irreversible heart failure and some leukemias, while trastuzumab does not: but the final balance sheet of mortality is the same.

1293   What is the current best treatment for relapsing multiple sclerosis? If it is not placebo, then this trial was arguably unethical. Although I’ve read all the main MS trials over the last 13 years, I wouldn’t be sure what to opt for if I had MS. I don’t think I’d bother with teriflunomide on the basis of this pharma-funded trial. Hair loss: that I can live with (or I would be dead by now); diarrhoea and nausea: OK, I’ve lived with those from time to time, but I don’t want to more than I have to. A 6% absolute reduction in disability over two years might result, which is a benefit I would never be aware of. Personally, I would say no.

This is a great teaching paper, to be used in conjunction with Know Your Chances by Woloshin, Schwarz and Welch. I’ve put myself in the position of the patient here and said no thanks. But real patients might want to make a variety of decisions, assuming that NICE approves the drug and your local consortium decides it can be afforded. The manufacturers, of course, herald this as a 30% reduction, whereas from the patient’s point of view it is a reduction from a one quarter chance of progression to a one fifth chance in two years. The patient needs to know the detail and have time to mull it over. Discuss how the content of this paper would need to be processed to enable this decision. Would a trial to assess tolerability be a good first step?

Lancet  8 Oct 2011  Vol 378
Once again there are no clinical trials in this week’s printed Lancet, and such studies as there are I have already told you about from the website. As some readers predicted, that makes it difficult for me to know when to talk about what. I could talk about the general decline of The Lancet, and Richard Horton’s Offline page, which now exerts a horrible fascination, like the poetry in JAMA, or watching Fox News. But I do not want to advertise these deplorable aberrations. Let’s turn to the one trial of interest to general practice on The Lancet’s website:

Nobody could describe The Lancet as the friend of British general practice, but when studies from UK primary care do make it into these supposedly august pages, they tend to be very good. This one is outstanding, and should inform daily practice. Patients with low back pain were assessed and randomized as they presented to ten GP surgeries. The physiotherapist assessors divided them into three groups: low, medium or high risk for lasting disability. They were then allocated to further care at the discretion of the physio, or tiered care according to their risk of chronic incapacity. Tiered care proved better. The notable features of this trial were (a) that the comparator was better-than-usual care (i.e. immediate triage and physio) and (b) that it stratified patients logically and avoided the one-size-fits-all approach that discredits most research in the eyes of the jobbing practitioner. As for the scoring instrument, economic assessments etc, I have no doubt that criticism is possible, but it will not come from me. General practice needs many more trials for like this, generating questions from the point of view of the patient, using interventions that are cheap and practical, and providing answers in terms of the outcomes that matter.

BMJ  8 Oct 2011  Vol 343
On my first clinical “firm” as a medical student, the consultant asked the student next to me to describe arcus senilis. He looked the ageing consultant in the eye and described it perfectly. It seems that we must call it arcus corneae these days, and it predicts nothing, according to the Copenhagen City Heart Study. By contrast, xanthelasmata are a marker for accelerated atheroma, independently of other risk factors. This is not significantly mediated by total cholesterol. The take-home message therefore is not “well, we all knew that already” but that we can measure cholesterol in people with xanthelasmata out of curiosity, but prescribe statins irrespective of what it turns out to be. And above all offer them help to stop smoking, if (as is likely) they are smokers.

Always approach modelling studies with scepticism, and that includes the “standard error” figures they give. You and I have to take these things on faith, and faith is not a virtue when reading the medical literature. I only draw your attention to this modelling paper on smoking and tuberculosis to emphasize that these are two evils which combine to kill millions in the resource-poor world, despite the fact that the first is totally avoidable and the second is largely treatable. If the toll goes up in the next 40 years, as this paper predicts, then the world will have messed up big-time.

Ann Intern Med  4 Oct 2011  Vol 155
Clinical decision rules abound, and to me they are rather like most works of classical music written after about 1920: I know I should try to understand and like them, but all they do is fill me with a vague sense of unease. They seem to work against intuition, rather than with it: they mess with the smooth inner workings of the mind. The classic playground for decision rule-makers is venous thromboembolism, and pulmonary embolism in particular, where Wells has gifted us a Schoenberg-like series of scores. I exaggerate: Wells is more like common sense slowed down. So what if you just take out the score, speed up common sense, and then do a D-dimer? According to this meta-analysis comparing clinical decision rules with what the Americans call gestalt, the results are just the same.

Plant of the Week: Colchicum autumnale

I was reminded of this plant by a report in this week’s Annals of a randomized trial of colchicine as prophylaxis for recurrent pericarditis.

It reduces recurrences by about a third.

I first came across colchicine in the school biology lab, where it was used to arrest mitosis, so we could pretend to see and admire the spindles of a dividing nucleus under a high-power microscope.

It is still a great treatment for gout in people who can tolerate it, and is the only safe agent in the gout we induce in heart failure patients by giving them loop diuretics. But hey, I am supposed to be talking about the beauties of the autumn crocus (or “naked ladies” as they are sometimes called).

All colchicum flowers are purple in various states of paleness: they rise and then sag in various poignant poses among the bare ground and the leaves of autumn. They are plants for the larger garden, to be wandered among as the mists rise and the sun gives a watery glow. Stuck in a small flowerbed, they just look out of place, and sad in all the wrong ways.

You can buy bags of the corms for planting earlier in the year, usually giving the name of a variety and a misleading description and picture. To me they all look much the same when they come up. Do not eat any part of this plant: Wikipedia informs us curtly that “Murderess Catherine Wilson is thought to have used it to poison a number of victims in the 19th century.”

JAMA  28 Sep 2011  Vol 306
1329    Intra-aortic balloon counterpulsation reduces left ventricular load and improves outcomes in animal models of myocardial infarction. But in previous small human studies of MI without shock, it hasn’t been shown to do anything much, and this trial confirms that it does not reduce infarct size significantly. But such is the success of primary PCI for MI these days that it would need something bigger than this 337-patient, nine-country trial to settle the issue with hard end-points: here there were just 3 deaths at six months in the PCI-plus-IABC group versus 9 deaths in the PCI-alone group.

1338   Reading surgical case-series reports from more than a hundred years ago, I’m struck by how many of the themes of modern outcomes research are already present – adjustment of case-mix, the need for proper follow-up, individual operator versus institutional outcomes, the relationship between operator volume and outcomes, and the learning curve effect. Here Brahmajee Nallamothu and colleagues take a look at the results of carotid stenting according to the annual volume and experience at the time of the procedure among new operators who first performed carotid stenting. It’s a nice study design, and confirms the intuitive expectation that the more of these procedures you do, the better your outcomes tend to be. It raises important issues about how we can best protect patients while taking new operators through their inevitable learning curves. And also what we do with those operators whose learning curves aren’t climbing enough. As for the more general issue of whether anybody should do carotid stenting in the first place, I will leave that for more learned persons to decide. Medicare decided to give it the go-ahead, but that does not make it a good procedure.

1344   Saw palmetto extract achieved fame about fifteen years ago when the balance of evidence at the time seemed to show that it was a safe, cheap, and effective remedy for the symptoms of benign prostatic hypertrophy. Kind Nature was thought to have placed relief for nocturic old males in the berries of Seroana repens, and even sceptical doctors like me would scrawl the annoying common name of this plant on a scrap of paper for patients to take down to the local alternative remedy shop. Hokum, according to this double-blinded RCT, using increasing doses of saw palmetto extract versus placebo. The stuff makes no difference at all.

N.B. Could any kind reader point me to the origin of the saying “Use new remedies early, before their effect wears off?”

NEJM  29 Sep 2011  Vol 365
1173   Could it be that the gene gnomes have pulled it off at last? A discovery that will genuinely guide treatment in a common condition – as common as inhaled glucocorticoid treatment in asthma? Well, there is much rejoicing in their ranks over the discovery that people with a certain GLCCI1 variant show only one third of the response to inhaled steroids as other asthmatics. For the second week running, the NEJM runs an editorial with “personalised treatment” in its title, this time by the great editor himself, Jeffrey Drazen. But without wishing to dampen the celebrations, I would point out the last phrase in the results: “with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability.” So more than nine times out of ten, genome profiling would not help you in this aspect of clinical management. Even if you could ever access it and afford it.

1184   Many of you will know the famous Fletcher-Peto curve of the progression of chronic obstructive pulmonary disease with and without smoking cessation – it dates back to 1976 and is a classic for several reasons, one being that it nicely illustrates the use of a graph to represent the natural history of a condition. I am surprised that this kind of depiction has never caught on as a teaching aid for other conditions: still more surprised that there is no similar graph in this paper on the variation in trajectories of COPD as measured by FEV1 after a bronchodilator in 2163 people over 3 years. Not surprisingly, the course of decline varies a lot between individuals and is normally distributed. For a longer term delineation of the natural history of COPD, nicely illustrated, you need to look elsewhere.

1193   Nicotine is one of many neurotoxic substances that plants have evolved to poison insect predators: the one in laburnum plants (Cytisus spp.) is called cytisine. It actually hits the same α4β2 nicotinic acetylcholine human brain receptors as nicotine, and laburnum extracts have been used as a smoking cessation aid since the 1930s, when Hitler encouraged the use of herbal remedies against the filthy habit of smoking which was sapping the fighting power of the German people. The Soviet people followed suit, and cytisine still remains available for next to no roubles in Russian pharmacies. In the capitalist West, we buy it chemically modified at great expense in the form of varenicline. Why not instead spend thruppence and use cytisine? This study shows that it definitely helps – 8.4% abstinence at 12 months after a 25-day course compared with 2.4% on placebo. A shame this wasn’t a head-on trial with Champix/Chantix/varenicline.

Lancet   1 Oct 2011  Vol 378
If there are important, believable randomised controlled trials out there waiting to be published, once again The Lancet has decided against letting us have them. The original papers this week have all been on the website for weeks, and I let you have a couple during the lean weeks of August and September. Here is one I didn’t:

1219   The circulation is circular, and so is a lot of the thinking that goes on around it. I read this modelling paper about the cost-effectiveness of options for the diagnosis of high blood pressure in primary care with particular care because the topic is important and I’ve been interested in it ever since I became involved in the first primary care ambulatory blood pressure studies which were done in Oxford 20 years ago. Another couple of Oxford colleagues are involved in this paper: but I am afraid I can’t agree with some of their modelling assumptions and hence their conclusion. The data to compare home monitoring with ABPM in relation to hard outcomes are simply lacking, as they say; Framingham is a less accurate predictive tool than QRISK for the UK population; a practice can buy 22 home monitors for the price of one ABPM machine, and patients much prefer these and often buy their own. The jury remains out and a wholesale (or even retail) move to ABPM is premature.

BMJ  1 Oct 2011  Vol 343
There are very few journals where a jobbing general practitioner could find a chance to publish these days, and the BMJ is not one of them. I got my chance back in 2000, when they still did Brief Reports, but these have now disappeared from the main journals. General practice is the most fertile of all research settings, potentially, and very much the best generator of patient-important questions; but funding arrangements are such that it is virtually impossible to realise these advantages, and even academic departments of primary care usually offer little help. Perhaps this may be about to change, according to this editorial on a new European strategic report. But some of us remember the UK Mant report from the 1990s, and will not be holding our breath.

I usually read editorials with personalised medicine in the title expecting to find a lot of genome-babble to disbelieve, but this strange piece is from a renin enthusiast hoping to reform the treatment of hypertension. Those with exceptionally long memories will remember the vogue for renin-based classifications in hypertension in the 1960s, but Morris Brown argues from first principles that now we could apply better assays more logically to the individualised treatment of blood pressure using specific drug classes which did not exist then. Perhaps: but some evidence would be nice.

Medical papers in praise of chocolate are rather common these days. They used to guarantee media attention, but on that I cannot possibly comment as I live a hermetic existence 3,000 miles from all British organs of public intelligence. I am also on a chocolate-free diet since I need to lose weight. Nevertheless the ideas of chocolate-driven cardioprevention set forth in this systematic review of observational evidence are very attractive: all we need is some way of making cacao palatable without the addition of sugar.

Arch Intern Med  26 Sep 2011  Vol 171
1542    Here is a paper which shows that patients who visit their doctor more frequently get more treatment. And if the condition is diabetes and the treatment is to the wrong targets, then that is not a good thing. The targets here were HbA1c below 7; BP below 130/85; LDL-cholesterol below 100mg/dl. The evidence? Harm to most patients in the first case; no benefit in the second; and no evidence in the third. And how often should one monitor each? Six monthly seems logical for HbA1c which is a reflection of glycaemic control over 3 months. Monthly seems the maximum for BP if seriously out of control, to allow for multiple measurements and regression to the mean. And LDL-C? Why measure it at all when we know that all these people will benefit from a high-dose statin. But this study conducted in two American primary care facilities linked to a teaching hospital shows that such targets are best reached by seeing diabetic patients every two weeks. So now you know another way to harm people with diabetes and waste health service money: see them too often. But in the USA, Merck is supporting an organization (ACE) which is publicizing this paper under the headline: Frequent Doctor Visits Benefits Patients With Diabetes (sic).

1571    So far the plant neurotoxins we have mentioned are nicotine, cytisine, and theobromine (in chocolate): now it’s time for caffeine. The stimulant properties of tea and coffee were discovered by Europeans at approximately the same time, and were followed in both cases by ultimately successful attempts to discover and steal the source plants and grow them in European colonies. Anything pleasurable and mildly addictive has always attracted medical censure in certain quarters; but as with chocolate, the evidence of benefit from caffeine outweighs any evidence of harm. Not that this is too wonderful a study: out of 50,000 US women, those who drink caffeinated coffee report less depression than those who don’t. Not exactly a randomised trial.

Fungus of the Week: Grifola frondosa

The alleged English name for this fungus is “Hen of the Woods,” which seems a bit odd as there is another quite different fungus called “Chicken of the Woods.” Why stick to the poultry yard when naming fungi that grow on trees? Why not “Pig of the Woods?” Or “Porpoise of the Forest?” I think I will stick with the Latin.

The Grifola grows at the base of trees, usually oaks. There is a gigantic version (G gigantea) which produces enormous brown fronds and kills its host: this one is sensibly proportioned and grey in colour and lives in a state of mild parasitism. It appears as a little cluster of fronds growing up through the soil, growing steadily larger until it has had enough, usually at about 50-70cm. It is simply there to shed spores, after all.

To harvest this fungus for the table, you have two options. You can pick a biggish specimen and then pull off the fronds when you get home, discarding the woody central mass. Or, if you are lucky, you can pick the whole thing while it is less than 20cm across and cook the lot. But the great challenge is to render it clean enough to be edible. Bear in mind that it has grown through the soil, and if the soil is tenacious, then you must resign yourself to a bit of mild pica.

Unfortunately the soil round the red oak from which I get my supplies is sandy, so the pleasure of eating this fungus is distinctly modified by loud crunching noises as grains of silica encounter dental enamel. The structure of the fronds is actually very beautiful but almost impossible to clean. Look carefully at the underside of many fronds and you will see the Mandelbrot set in all its wonder: a multiplicity of similar shapes at every scale, none predictable. This may give you enough satisfaction, without you feeling the need to proceed to the cooking stage.

However, if you are prepared to brave the grimaces of your loved ones and the inner doubts which I have sown in your mind, proceed as follows:

Recipe A: for fronds. Tear the fronds from a young but well-developed specimen. Under running water, attempt to remove all soil, insects, grit etc using your fingernails, a shaving brush and/or a toothbrush. Do not expect to succeed. Heat olive oil moderately in a frying pan and add the fronds while they are still wet. Reduce the heat so that they stew for 10 minutes. At this point add some scraps of chopped shallot and season with salt and pepper. Simmer further until the mushroom liquor is nearly evaporated, but do not let them brown. Serve with finely chopped parsley, eat jauntily and claim that they have a mild and delicate taste and that everybody should try some.

Recipe B: for a whole infant cluster. Cut the base from your cluster and attempt to remove dirt etc. from under the little fronds under running water. Do not expect to succeed. Cut the cluster into slices about 0.75cm thick. Cut some very fatty bacon or pancetta in cubes or pieces and fry until the fat has been largely melted into the pan. Now add the sliced grifola, followed by a few scraps of shallot. This time you can allow a little browning to occur, but beware of drying out. Serve with or without parsley, and murmur “delicious” as you eat the bacon with as little of the fungus as you can get away with.

JAMA  21 Sep 2011  Vol 306
1205   I don’t know why spammers have me down as so interested in imitation Rolex watches and erectile function: neither is particularly true. But I guess that if I had a diagnosis of localised prostate cancer, I might want to know the chances of each treatment option causing me to become impotent, and this is what this study does. We now know a lot about this patient reported outcome measure through careful follow-up of patients with well categorised characteristics from 9 academic centres in the USA, after they received various kinds of prostatectomy, external beam radiotherapy or brachytherapy between 2003 and 2006. The accompanying editorial rightly hails this as a good example of patient-centred outcomes research, and also uses the paper to illustrate some of the methodological problems of this kind of research. The big omission in this study, for example, was a group managed by watchful waiting. To measure the effect of an intervention on an outcome, you also have to measure the untreated progress of the disease: a principle first set forth by James Jurin, Secretary of the Royal Society of London, in 1722. When he called in witnesses from Yorkshire and New England to present their statistics on the mortality of smallpox with and without prior variolation, before himself and the president, Sir Isaac Newton, medical outcomes research was born.

1215   By the banks of the Arno, where Dante first caught sight of Beatrice, there now walk men and women with distracted frowns, oblivious to the beauty around them. These are the Florentine researchers who have produced the latest paper to show that high residual platelet activity after clopidogrel predicts increased risk of further cardiovascular events. Not by much, though, and there is not the slightest evidence that one can do anything about it, though they tried increasing the clopidogrel dose in these patients. I long ago gave up trying to follow the detail of this debate: it is a Dark Wood in which the true way is easily lost. If you are determined to press on, however, an editorial by Dominick J Angiolillo provides a very good summary of the evidence and the issues around clopidogrel and platelet function testing (which is a futile exercise). Let Dominick be your Virgil as you explore these Infernal regions.

NEJM  22 Sep 2011  Vol 365
1079   Idiopathic pulmonary fibrosis is a horrible condition: sooner or later it is bound to kill you by depriving you of oxygen, but you cannot tell when. My last patient with IPF took to his bed for two years before he died. So full marks to Boehringer Ingelheim for trying to develop a tyrosine kinase inhibitor  (BIBF 1120) which might improve the outlook of this condition. Unfortunately it doesn’t, so far as we can tell from this trial, which seems to have been mostly about dose-finding. There was a tendency to improvement in some indices of lung function at the optimal dose, but this never reached statistical significance and patients felt worse than on placebo. Boehringer Ingelheim “provided writing and editorial support” through an agency for the writing of this paper, and the conclusion of the abstract reads:
“In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life.”
I hope the FDA and EMA take a good hard look at this drug before anyone starts trying to market it as a gleam of hope for patients with this nasty disease.

1088   Somebody needs to write a book about the future of medicine along the lines of Galileo’s Dialogue concerning the two chief world systems of 1632. In one system, the world of medicine is centred on the laboratory, which produces new drugs and genomic tests, and the patient revolves in distant orbit around this blazing source of golden light. This conception is variously known as genomic medicine, translational medicine, or even, by an Orwellian twist, personalised medicine. It generates vast revenues for industry and ploughs some of these back into academic centres: it produces studies like this one of lebrikizumab, a monoclonal antibody which only works (and then not much) in adults with asthma who have a particular genomic signature. It is a world view celebrated in the accompanying editorial, “Moving closer to personalized medicine,” and no doubt also by the various employees of Roche and Genentech like the one who “reports that Roche/Genentech is developing a periostin assay as a potential companion diagnostic for lebrikizumab.” The contrasting world system holds that medicine revolves around the patient: it is variously called user-driven healthcare or patient-centred medicine or outcomes-based medicine. It starts and finishes with the experiences of individual patients as participants in their own care, seeking all the evidence that can contribute to shared decision-making aimed at achieving the patient’s own preferred outcomes. The Vatican of the medical research establishment smiles indulgently at such fancies: yes, my child, such things await us in Heaven if we are obedient in this fallen world; come, do not dabble in heresy, or we will have to show you the instruments of the Inquisition: you may find it hard to get funded, to get published, to get promotion; perhaps we may try a little vexatious litigation if you become troublesome.

Lancet  24 Sep 2011  Vol 378
The world is teeming with medical researchers whose future depends on getting published in a high impact journal: a stupid, unjust, archaic system, which cannot end soon enough. This week, a throng of petitioners go empty-handed as The Lancet strides through them, like Cardinal Wolsey holding an orange studded with cloves to his nose: such commoners can wait, this week we will turn our gaze on the great world and those high themes on which it pleases us best to pontificate.
So, if you want to learn even more about Japan and its health services, longevity etc than you did last week, here is your chance. Yet another survey tells us how far we are still short of reaching Millennium Goals 4 and 5 on maternal and child mortality.

1166   The only research paper in this issue is a descriptive case-series of 12 patients with severe haemolytic-uraemic syndrome and neurological symptoms due to Shiga-toxin producing E coli in the outbreak which killed 50 North European adults last year. They were treated with immunoadsorption and with the complement blocking antibody eculizumab. Ten were left with no neurological damage.

BMJ  24 Sep 2011  Vol 343
It is heartening to see the return of more useful clinical research to the BMJ, like this Belgian trial to determine the effect of manual lymph drainage in addition to written guidance and exercise therapy on lymphoedema following breast cancer with unilateral axillary lymph node dissection. Thank goodness for a nicely designed study on an important topic, reported clearly and with due modesty, showing that manual drainage makes very little difference to this outcome.

I like the next paper too, even though it is written largely by statisticians. They examine the hourly effects of ambient air pollution on myocardial infarction, describing their efforts as a “time stratified case crossover study linking clinical data from the Myocardial Ischaemia National Audit Project (MINAP) with PM10, ozone, CO, NO2, and SO2 data from the UK National Air Quality Archive.” Excellent: this is what statisticians and epidemiologists are for – to supply interesting talking points for clinicians and policy-makers. The conclusion here (which I would not presume to interrogate) is that air pollution brings forward acute coronary events which were likely to happen anyway.

Again, it is very useful to be reminded that “The total burden of premature deaths from natural causes in people with schizophrenia or bipolar disorder is substantial.” Also that “there is a need for better understanding of the reasons for the persistent and increasing gap in mortality between discharged psychiatric patients and the general population, and for continued action to target risk factors for both natural and unnatural causes of death in people with serious mental illness.” Could it be something to do with the increasingly poisonous medication we are giving them? Drugs like olanzapine, quetiapine, and risperidone call to mind Oliver Wendell Holmes’ saying that if all of them “were thrown into the bottom of the sea, it would be so much the better for mankind, and all the worse for the fishes.”

I am not quite so enamoured of this next paper, also written largely by statisticians, in which they draw on copious data from different sources to construct a Bayesian model for the fluctuations of severity in the 2009 pandemic of influenza A/H1N1 in England. The conclusion here seems counter to clinical experience: the model suggests a mild pandemic “characterised by case and infection severity ratios increasing between waves.” Maybe we all just got used to the presence of H1N1 flu in our midst, and were oblivious to these changes. And I still haven’t come across a clear summary statement on whether the arrival of H1N1 increased or decreased total influenza mortality.

An excellent editorial by Andrew Farmer and Robin Fox, a GP colleague from Bicester, calls for a better recognition in general practice of the atypical kinds of diabetes, and the importance of this is starkly illustrated in this study which shows that “the proportion of deaths caused by acute complications of diabetes has increased in patients with late onset type 1 diabetes,” in contrast to diminishing mortality in type I diabetic patients who developed the disease in childhood. I had such a patient who in her 70s twice developed acute ketoacidosis due to infection, because although she was on insulin, we mistakenly tended to regard her as a type 2 diabetic. But such patients have no reserve beta-cell function whatever, and spiral out of control with dangerous rapidity.

Ann Intern Med  20 Sep 2011  Vol 155
345    The American obsession with diagnosing streptococcal throat infection continues in this study which adds real-time biosurveillance to the Centor score. Apparently knowing the local prevalence of group A strep improves diagnostic accuracy by altering the pre-test probability of various features of the score. But it’s not diagnostic accuracy we’re looking for: what we need is a predictor of useful response to antibiotic treatment, which is not quite the same thing.

361    For as long as I have been writing these reviews, data have been accumulating about the time-dependent benefits of percutaneous intervention for myocardial infarction.  If the adage that time equals myocardium is true, then delay should predict increased heart failure as well as increased mortality. And so it proves from these data from Western Denmark, between 1999 and 2010.

389   But if system delays are still common in Denmark, a flat peninsula that you can cross in a couple of hours, are they not even more inevitable in most other countries? And given that fact, should we not be thinking in terms of an integrated dual reperfusion strategy to best serve all patients with STEMI? That’s certainly the view of this discussion piece, which deals mainly with the situation in North America. Here is an area where detailed modelling and analysis are still needed to guide policy.

Plant of the Week: Ficus carica

I fear that this is a dismal season for British fig growers: your little trees of “Brown Turkey,” carefully grown with a restricted root-run by a sunny wall, will now be bearing many a green bulge that is due to drop off when the first frosts arrive. I think that in twenty years of attempted fig-growing in the UK, I have produced the same number of barely edible fruits. We Britons persevere because of this plant’s Mediterranean and indeed biblical connections, and when we curse our barren fig trees we can plead that we are simply following the example of Our Lord.

It is much different here in the USA, I am happy to report. The food shops now abound in little plastic baskets containing a dozen or more ripe black locally grown figs, which I find hard to resist. And British fig lovers are of course perfectly able to buy nice ripe imported figs in local markets for several months of the year. I never tire of them, though my wife is less keen: but even she acknowledges the supreme merit of sliced ripe figs with Parma ham, or, best of all, interleaved with smoked duck and drizzled with a few drops of finest balsamic vinegar.

JAMA  14 Sep 2011  Vol 306
1089   In medicine, always expect the counterintuitive. For some time it has been known that removing more lymph nodes at the time of bowel cancer surgery is associated with better outcomes. This is nicely confirmed in this large cohort study – 86 394 patients, showing a one third reduction in total mortality within tight confidence intervals, for those who had more than 30 nodes removed compared with those who had 1-8 removed. The odd thing is that the extra nodes showed scarcely any additional cancer and their removal contributed nothing significant to staging and therefore to clinical management. It seems that the removal of these seemingly uninvolved lymph nodes is of major therapeutic benefit in its own right.

1104   Both of the high pressure heart valves are tricuspic, but the one on the left is called the aortic valve and in 1.3% of the population it is bicuspic. If universal echo screening at birth ever gets adopted, we will become aware of many more of these bicuspic aortic valves, and we will have to counsel a lot more parents and patients about the significance of this, the commonest congenital heart defect. Here are the data to guide us from the Olmsted County cohort study, which collected over 40,000 echocardiograms from 1980 to 1999, and identified 416 people with definite BAV. For some reason, these individuals are called “patients” and those in prison are excluded as “non-legitimate.” So what are you to say to the parent of a healthy baby who has been found incidentally to have two instead of three flaps on her aortic valve, and has not yet been locked up in an American jail? The authors of the paper don’t make this very easy. You could say that this puts the wee bairn at more than 8 times the population risk of aortic dissection, and so cause everyone a lifetime of anxiety. Or you could say that the risk of the “abnormality” causing a problem is quite small at 3.1 cases per 10 000 person-years. Unless I have got my sums wrong, this amounts to a 2.5% risk in a lifetime of 80 years.

1113   Studies of general prognostic markers drive me mad. Why do journals give space to these things, generated purely by the availability of stored sera and some new candidate chemical? Serum cathepsin S is the latest and it proves weakly predictive of death in older adults – very weakly, if you look at the tables and figures. You can’t tell this from the abstract which gives the mean OR increment per unit – and whoever knows what units cathepsin S is measured in? Now, if the Revd. Thomas Bayes, FRS (1701-1761) had given a sermon to his Presbyterian flock at Mt Sion chapel in Tunbridge Wells on the text “O Lord let me know mine end, that I may apply my heart to wisdom,” he would also have pointed out that the only value of a new prognostic marker is what it adds in predictive power to those we already have. And for those unwise enough to want to know when they are going to die, we already have telomere length, BNP, cystatin C and co-peptin. Let us apply our hearts to wisdom, and enjoy ourselves while we can.

NEJM  15 Sep 2011  Vol 365
993   When is aggression good? When it is American medical aggression, of course. Here “aggressive medical therapy” is compared with the Wingspan stent device in patients who have suffered stroke or TIA due to atherosclerosis of a major intracranial artery. The trial was stopped early when it became clear that the stent device was causing too many extra strokes in its own right. So what was this “aggressive medical therapy” that proved superior? Blood pressure lowering, aspirin and statins. Now if that counts as aggressive, we should all change our name to Dr. Genghis Khan.

1025   The NEJM has given the job of reviewing breast cancer screening to Ellen Warner, who baldly states that “screening mammography for women 50 to 69 years of age is universally recommended.” I can hear the sound of loud barking from across the Atlantic at the Nordic Cochrane Centre, as the Great Dane, Peter Gøtzsche, prepares a fulminating response. Moreover, it seems that Dr Warner holds a candle for mammography screening before the age of 50; and there is astonishingly little mention of the harms of screening and overdiagnosis. The virtue of mammography, it seems, is still a truth that Americans hold to be self evident. Be prepared for some interesting letters in the NEJM of some weeks hence.

Lancet  17 Sep 2011  Vol 378
1071   Here is a straightforward publicly funded randomised trial, which demonstrates that in patients with stenosed saphenous vein coronary grafts, drug-eluting stents are better than bare metal stents. Our thanks go to the ISAR investigators and the Deutsches Herzzentrum for this useful increment in medical knowledge. Even those doyens of Oxford cardiology, David Taggart and Adrian Banning, cannot find much else to say in their editorial, Are we Wiser after ISAR? – except to make their usual point that if you want to avoid graft stenosis, you use the internal mammary artery, not the saphenous vein.

1089  extremis malis extrema remedia is the Latin tag that gave rise to the English proverb “Desperate diseases call for desperate remedies.” There are many variations, from the first known English translation “A stronge disease requyreth a stronge medicine” (1539) to modern adaptations such as “drastic times call for drastic measures.” Does anyone know the Danish version? I ask because the paper we are considering here is a case series report of early plasma exchange used to treat haemolytic-uraemic syndrome in adults from southern Denmark. As the German plague of Shiga-toxin producing E coli spread northwards across the peninsula of Schleswig-Holstein, the Danes decided to get active at the first sign of trouble. And it paid off: all 5 patients got better within a week, with no sequelae. The authors suggest a randomised controlled trial; but if I get this disease, swap my plasma, please.

BMJ  17 Sep 2011  Vol 343
People with chronic sciatica are generally willing to try anything, and many pain clinics offer caudal steroid injections as a “worth a try” treatment option. This Norwegian multi-centre randomised trial shows that saline injections work just as well. The accompanying editorial winces like someone with radicular pain getting out of a chair: “epidural steroid injections may be an effective adjunct when used judiciously,” it pleads. Well yes, but why not use epidural saline instead?

I’m slightly baffled by the appearance of the next paper in the BMJ. It’s a Canadian study pointing out the danger of hyperkalaemia if you co-prescribe co-trimoxazole and spironolactone, particularly in elderly patients. Now the BMJ may be widely read in Canada and perhaps in other parts of the world where co-trimoxazole is prescribed routinely to elderly patients; but in the UK we hardly ever prescribe it except for the treatment or prophylaxis of Pneumocystis infection. So I’d have thought this was a paper for CMAJ – itself a journal all doctors should read.

When I mentioned Peter Gøtzsche earlier, I wasn’t aware that the Great Dane would make two appearances in this week’s BMJ. In this one, he joins colleagues at the Nordic Cochrane Centre to look at the effect of mammography screening on rates of breast cancer surgery in Norway. Contrary to breast cancer screening propaganda, the introduction of whole population mammography does not decrease the need to perform total mastectomies: quite the opposite. In fact there was a large surge in Norway, consistent with overdiagnosis, followed by a temporal decline which can best be explained by a universal trend towards breast conserving surgery.

The mighty Viking now turns his double-headed battle-axe to meta-analyses which use a multiplicity of data. If you mix all sorts of trial designs, patient populations, starting points, end-points, and disease definitions into your statistical software and run it over lunch, by the afternoon you can have a meta-analysis. The only problem will be that it is codswallop. But that is no reason not to publish it, of course: nobody is likely to check. Ah, but you have reckoned without the Great Dane…

I don’t usually comment on the series Easily Missed, because I helped to set it up and I still review all the contributions long before they are published. But when I first looked at a submission on Panton Valentine leukocidin associated Staphylococcus aureus infection I had the feeling that I hope you will all get from time to time in this series: “I do wish I had known about this earlier.” People unfortunate enough to carry this bug get endless recurrent boils until they are treated with a long course of rifampicin and another suitable antibiotic.

Arch Intern Med  12 Sep 2012  Vol 171
 1433   Principles of conservative prescribing is classed as a review article, but it is really a manifesto. I love it. Put these Rules on your wall:
“(1) think beyond drugs (consider nondrug therapy, treatable underlying causes, and prevention); (2) practice more strategic prescribing (defer nonurgent drug treatment; avoid unwarranted drug switching; be circumspect about unproven drug uses; and start treatment with only 1 new drug at a time); (3) maintain heightened vigilance regarding adverse effects (suspect drug reactions; be aware of withdrawal syndromes; and educate patients to anticipate reactions); (4) exercise caution and skepticism regarding new drugs (seek out unbiased information; wait until drugs have sufficient time on the market; be skeptical about surrogate rather than true clinical outcomes; avoid stretching indications; avoid seduction by elegant molecular pharmacology; beware of selective drug trial reporting); (5) work with patients for a shared agenda (do not automatically accede to drug requests; consider nonadherence before adding drugs to regimen; avoid restarting previously unsuccessful drug treatment; discontinue treatment with unneeded medications; and respect patients’ reservations about drugs); and (6) consider long-term, broader impacts (weigh long-term outcomes, and recognize that improved systems may outweigh marginal benefits of new drugs).”

1454   Cardiac resynchronization therapy can work wonders for some patients with heart failure, reducing hospital admission and death by 40%, and just as importantly, bringing immediate major improvements in quality of life. So how do you qualify for it? This meta-analysis demonstrates that the QRT duration threshold for biventricular pacing to be effective is 150 milliseconds. Less than this and CRT achieves nothing.

1463   Here is another excellent paper by Lisa Schwartz and Steven Woloshin on communicating benefit and harm to patients. Why, you may ask, do their names always appear together? Could they by any chance be more than just work colleagues at Dartmouth? I can answer this question definitively, because I was recently admiring a work of calligraphy hanging on their living room wall and discovered that it was their marriage certificate. Here they perform a “national randomised trial” by using a commercial database of randomly selected US adults to quiz about their understanding (a) of the meaning of Food and Drug Administration approval and (b) how to choose the better of two drugs. They had an excellent response rate and discovered that most Americans overrate the protection afforded to them by the FDA, and have difficulty in understanding drug choices but can be helped by simple explanations.

Plants of the Week: Mallows

When the aged Richard Strauss wrote his great Four Last Songs for soprano and orchestra, all of them meditations on autumn and death, he actually wrote a fifth song called Malven, meaning mallows. And there they are as you look through the window, glowing in the September sunshine, ready to fall victim to the first frosts which cannot be long in coming.

Every garden should have space for a few kinds of mallow. In fact, if you are starting a new garden, be sure to scatter abroad some seeds of white mallow. This is some kind of Althea or Alcea, an aggressive perennial weed which you will forever be pulling up in years to come, but really valuable for its evergreen crimped leaves and its abundance of white flower throughout the season.

Put hollyhock seed in every dry crevice you can find, and keep buying hollyhock plants in village sales until they naturalize themselves with you. Their leaves may turn brown and yellow with rust, and they may die on you repeatedly, but they are not be lived without.

Finally, spare a thought for good old Lavatera “Barnsley,” an untidy shrub which was wildly popular in the mid-1980s but is seen less and less now. It may be short lived and verge on the proletarian; though The Garden once deigned to publish an article about its origins, which lie not in the Yorkshire mining town but in a genteel Gloucestershire garden of the same name. It flowers abundantly for months and has admirable grey leaves. Cut it back annually and you have a friend for nearly the whole season. And if you want a new plant, just stick one of the autumn prunings in the ground.

JAMA  7 Sep 2011  Vol 306
952   This is a themed issue on Medical Education, a domain where giant forces compete for the minds of highly selected young people, and science can tell us little about what really matters. I gave my first talk on the subject in 1973, to a largely female student audience in East Germany. My Communist Party minders looked a bit uneasy, but it seemed to go down well with the girls: no doubt they were taken off later for an ideological debriefing. They were told, perhaps, that they were fortunate to live in a socialist democracy where they had been chosen from working class families to carry out a socially worthwhile job which would be paid as well as a steelworker. The people’s government and the Party would see to it that they had the best education and facilities, and that they would be looked after for life. In capitalist countries, by contrast, medical students either have to be financed by their bourgeois parents or incur an enormous burden of debt, which can only be paid off by charging massive fees to their proletarian patients via greedy intermediaries called insurance companies. Now if one of those shifty-looking men could read this article in JAMA, he would feel entirely vindicated: one third of US medical students feel burnt out and/or anxious and the principal correlate is high debt. The next meeting of the Socialist Medical Pioneers will be held on Tuesday evening and all are expected to attend.

978   A great deal of what is important in medicine can be taught to some degree but cannot be measured directly – patient-centredness, diagnostic acumen, good communication, knowing when to leave alone. But there are many technical aspects of practice which can and should be measured, and can and should be taught using technology enhanced simulation. This huge meta-analysis looks at 609 studies relating to a wide variety of technical aids from resuscitation dummies to laparoscopic surgery simulators. In all but a couple of instances, these teaching technologies brought about a marked increase in measures of speed, competence and economy of movement.

NEJM  8 Sep 2011  Vol 365
892   “Being a germ isn’t easy,” according to the first sentence of the editorial on this study of how vancomycin-resistant enterococci became daptomycin-resistant. I think I must demur: being a germ has been easy for about 4 billion years, which is why they rule the planet. And since the primeval soup first produced the beginnings of life, there have never been such exciting places for germs as hospitals. Humans make obeisance to them in paper gowns and masks and latex gloves: how they laugh! Germs, you see, are not individuals: they form aggregated masses like virtual hobbits, sometimes forming biofilms, sometimes living in noses and throats, but mostly liking nothing better than to inhabit the soil. They swap stories and chemicals with each other all the time, and when something nasty comes along, like an antibiotic, they will say to a chum in distress: here, try a bit of this, I’m rather proud of it as a matter of fact, made it myself. And in an hour or two, there are a few hundred billion germs all doing that same thing. Hospitals are so beautiful: warm, generally a bit dirty, full of sick people with lots of other people walking among them, with the very latest in fashionable antibiotic resistance mechanisms. In the case of vancomycin resistant enterococci, however, there had been other nice places beforehand: the faeces of antibiotic-fed cattle cooped up together, for example.

919   Drug-resistant epilepsy is an exceptionally difficult topic, dealt with exceptionally well in this review. Be sure of the diagnosis of epilepsy; be sure of compliance; be sure to refer appropriately; be sure to monitor the patient adequately (though not with drug levels, which are mostly a waste of time); be sure to understand the pharmacodynamics and pharmacokinetics of the agents you use; keep abreast of new drug developments; and don’t forget the place of surgery. There: you don’t have to be all that brainy to be a neurologist.

Lancet  10 Sep 2011  Vol 378
983    Most of the time we give advice and prescriptions to adults with asthma based on symptoms and occasional measurements of peak flow; but nobody would pretend it’s an exact science. This team of Australian researchers decided to use measurement of exhaled nitric oxide instead, and cunningly chose a setting where follow-up would be easy: two antenatal clinics. The mothers with chronic asthma were randomized to either usual care, based on taking a long-acting beta agonist inhaler and adjustment of steroid inhaler by symptoms; or LABA with adjustment of steroid inhaler dose by serial measurement of FENO. The latter group had fewer than half the number of asthma exacerbations. So concept proved: now we need to see how much value this measurement of airways inflammation can have in the management of “brittle” asthma generally, and whether the technology can be developed to make it practical for primary care.

991   “Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality in high-income, low-income, and middle-income countries.” says the commentary on this paper about the life-long risk of developing COPD. The investigators did a retrospective longitudinal cohort study using population-based health administrative data from Ontario, Canada (total population roughly 13 million). Great. So where are the data about duration and intensity of smoking and the effects of cessation? Um, not here.

1027 “Chronic obstructive pulmonary disease (COPD) is a major global health problem with a rising incidence and morbidity” begins this review of new therapeutic approaches to COPD. OK, we got you. The three authors then bewail the lack of progress in the field but see possibilities on the future if better biomarkers can be identified and if only the regulatory bodies (FDA, EMA) would just calm down a bit and not demand so much evidence of what actually happens to patients. This is certainly the way to get more drugs on the market: find new surrogate markers and lower the bar of proof. Afterwards discover what happens to hard end-points in post-marketing studies, which take a good part of the drug’s patent-life to get done. Set aside a share of the profits in case things don’t look good and people sue. You know it makes sense. Well, these three authors certainly have reason to think so: between them they have received payments from over 100 outside sources, nearly all of them commercial.

1038   “Chronic obstructive pulmonary disease (COPD) is a chronic disorder with substantial comorbidity and major effects attributable to the high morbidity and mortality rates.” Hmm, nice try, but it doesn’t quite work that way round. Here the discussion is of controversies in treatment, which show how little we know about how to treat COPD once it has started. Debate about inhaled steroids and long-term antibiotics has been simmering or occasionally raging as long as I’ve been a doctor: it’s the authors’ misfortune that the most significant recent study of the latter appeared in the NEJM just two weeks ago. As for the use of beta-adrenergic agents, the tables suddenly turned when a recent BMJ study showed that beta-blockers conferred a survival advantage: though the effect size is probably 6%, not 25% as claimed. Enough: in the overwhelming majority, this is a disease of smoke. Get rid of tobacco, domestic dung fires and atmospheric pollution, and chronic obstructive pulmonary disease (COPD) will no longer be an important cause of morbidity and mortality in high-income, low-income, and middle-income countries, to coin a phrase.

BMJ  10 Sep 2011  Vol 343
Ever heard of J Alison Glover? I can’t say I had until I read Jack Wennberg’s indispensable book, Tracking Medicine, a few months ago. Now Alison has a long pedigree as an English girl’s name, as you will know it you have read the jaunty poem from Harley MS 2253 (compiled c1340) with a refrain that ends
From alle wymmen my love is lent
  And lyht on Alysoun.

But this is merely to warn you that our J. Alison is a man. His father was called James Grey Glover, so he really has no excuse for adopting this egregious name. We cannot even justify leniency on grounds of American origin, because JA Glover was an Englishman who trained at Cambridge and Guy’s. First rate shot too. In the 1930s, he investigated the end-results of adenoidectomy and tonsillectomy among English schoolchildren, and concluded that although rates of T&A removal varied to a spectacular degree around the country, outcomes didn’t vary at all. Now here is a Dutch trial of the effectiveness of adenoidectomy in children with recurrent upper respiratory tract infections, carried out 80 years later. And do you know what? It doesn’t make any difference at all.

Gender differences (which used to been known as sex differences, until that was thought to cause confusion) are very pronounced in ischaemic heart disease. Here four female professors of medicine and an associate carry out a complex modelling exercise to explore the trends, based on whole-population mortality data from England, Wales, and the USA. I can’t say that I altogether follow their argument, but if it is to be believed, then the idea that female IHD accelerates following the menopause is a myth. Instead, IHD in young men shows such an acceleration. As for the progress of women in cardiology: well, in my day, there weren’t any, and now you there are, oh, dozens.

Whatever you (or I) may say about the research papers in the BMJ, the Clinical Review section does great work for British doctors who want to stay up to date with basic clinical skills and knowledge, and for others around the world who either pay a subscription or can get full text via HINARI. Here is a good general guide on how to assess and investigate cognitive impairment in the elderly: the authors mention some alternatives to the Mini Mental State Examination, which is subject to copyright, but don’t include the CASE instrument developed by an Ottawa team, which has good claim to be the best validated, and is freely available on line (as it jolly well should be).

Ann Intern Med  6 Sep 2011  Vol 155
281   Open bariatric surgery can take several forms, including gastric bypass and duodenal switch. As we’re in historical mood, it’s worth noting that the surgical foundations of these procedures were laid down by the great Viennese surgeon Theodor Billroth not long after abdominal surgery first became possible in the middle of the nineteenth century. Billroth was also an excellent musician and a warm and generous friend to Brahms, but after many years the curmudgeonly old composer took umbrage over some minor affronts and poor Billroth was left hurt and puzzled (Here is a superb old paper about this). What was hazardous major surgery in 1867 remains hazardous major surgery in 2011. This outcomes study from a fairly small case series in Norway and Sweden shows that biliopancreatic diversion with duodenal switch is the more effective procedure, but also the more hazardous, with a 62% rate of adverse effects over 2 years, and 16 readmissions in a group of 29 subjects.

292   So there’s a global epidemic of type 2 diabetes upon us and we want to know what to do about it. This cohort study shows how it can be done. The National Institutes of Health (NIH)–AARP Diet and Health Study cohort was established in 1995 to 1996 by the National Cancer Institute and ended up following more than 200,000 American adults. Those who kept their BMI under 25, took 20 minutes of exercise 3 times a week, drank alcohol regularly, did not smoke and kept to reasonable diet of some kind (there is a black box area here) had 16% of the chance of developing diabetes compared with those who did none of these things.

Plant of the Week: Hydrangea paniculata “Tardiva”

Wandering the streets as autumn approaches, both in New England and in old, there are few shrubs worth a glance, but this is a valuable exception. A well-grown bush is a lovely thing, with wide lobular leaves and a profusion of huge conical flower heads. They start green, remain a pure white for a week or two, and then fade to pink and brown. Bees like them, and if you push your nose close enough you may detect a slight scent of grass and honey.

Every garden should have a variety of this plant suited to its size, to keep company with repeat flowering climbing roses of pink, red or apricot, and those dark-coloured Polish clematis hybrids which seem to go on flowering for ever.

NEJM  1 Sep 2011  Vol 365
787    Studies of out-of-hospital cardiac arrest require heroic feats of organization and generally provide survival-to-discharge rates around 7%. In this randomized trial, the research question was whether in a person found pulseless out of hospital, it’s best to start CPR immediately or to analyze the heart rhythm immediately. In fact it made no difference at all whether emergency medical staff put a monitor on right away or waited till after a couple of minutes of CPR. Survival to discharge without major disability was 5.9% in either group.

798   The same US/Canadian research group (ROC, for Resuscitation Outcomes Consortium) earns itself a second NEJM paper with a randomised study of the thing known as an impedance threshold device which is supposed to increase the degree of negative intrathoracic pressure during out-of hospital CPR. They went to the trouble of comparing it with a sham device and blinding the allocation, but the results were once again 6.0% in one group and 5.8% in the other. All that these heroic efforts have achieved is to cut the mean survival of out-of-hospital arrest by a percentage point or so. Most people who drop dead stay dead.

Lancet  3 Sep 2011  Vol 378
For no medical reason I can think of, Richard Horton has decided to run an entire issue of The Lancet to commemorate the 10th anniversary of the massacre by 19 Saudi Arabians of 2,977 people in the USA. I am surprised he didn’t choose the date closest to September 11th. “The events of that day changed the historical trajectory of America and the world. They have had—and continue to have—profound consequences for health” intones The Lancet. No they haven’t – the list of consequences he enumerates were entirely the result of the foreign wars decided upon, probably a bit earlier, by George W Bush and Donald Rumsfeld.

First Online:

The PURE Study is the successor to INTERHEART and is a noble attempt to do global cardiovascular cardiology by following up a cohort of 154,000 individuals in 18 high-, middle- and low-income countries for a minimum of 10 years. (As Tennyson wrote for Sir Galahad, “My strength is as the strength of ten/ Because my heart is PURE”). At present, three-quarters of cardiovascular disease occurs in the last two categories of country, and this report confirms what we already had guessed: the poorer the economy, the fewer people take drugs for secondary cardiovascular protection. It seems a particular shame that fewer than 9% of those with known cardiovascular disease in the poorest countries even take aspirin: but then in the richest countries, the figure is only 65% following myocardial infarction, and 53% following stroke. What is going on?

Acne vulgaris gets a good review here, which examines the evidence base for treatment of this ubiquitous condition and finds that a lot of it is not much better than the recommendations on YouTube (toothpaste is apparently a teenage favourite). Or indeed the lotio alba tinct. prescribed in William Carlos Williams’ 1934 tale of American general practice, The Girl with a Pimply Face. Benzoyl peroxide is apparently a better topical treatment than local isotretinoin. Mercifully, although acne is a strongly hereditary condition, it does not seem to have attracted the attention of gene gnomes, so we are spared several pages of discussion about polymorphisms at the ZIT locus and how they affect putative molecular reactions between sebum degradation products and Propionibacterium acnis. Talking of the latter, there is little evidence of the superiority of one antibiotic over another; and none whatever to choose any particular combined oral contraceptive.

BMJ   3 Sep 2011  Vol 343
It’s now over a year since I had to pay much attention to the Quality and Outcomes Framework for UK primary care, and what a relief it is. Amongst the many idiocies of the system is the requirement to use “validated depression scores” in a variety of circumstances including chronic disease. This systematic review drifts about trying to discover just how and in what populations these depression scores were validated and against what “gold standard”. In a great number of cases, the validation cohort included people already receiving antidepressants. At best, these scoring systems are just a reminder of the kind of questions to ask; I’m yet to be persuaded that there is any evidence to support their use as screening tools in general practice, still less for their use in monitoring response to treatment.

In fact the BMJ is rather heavy on “what to believe” papers this week: I’ll spare you further discussion on verification problems in diagnostic accuracy studies but it’s worth mentioning a “meta-epidemiological” study of the inconsistency between direct and indirect comparisons of competing interventions. The dream of Evidence Based Medicine is that jobbing doctors should habitually seek evidence to inform their daily practice. I still sign up to that, but boy is it difficult when the right evidence is so hard to find, to compare and to trust. The most fundamental question we have to face is “is this treatment better than that?” and all too often there are no head on comparisons. This paper warns of the perils of indirect comparisons and then gets too technical for most clinician readers. Which is exactly the problem.

Without a huge increase in the medical workforce, British general practice looks set to remain the art of trying to practise good medicine in ten-minute bites. And as more and more consultations are not about acute treatable illness but involve chronic disease management and care of the elderly, ten minutes is simply too short to do good medicine. We may love our old ladies, and they us, but do we actually do a proper functional assessment of the elderly? I hope the answer is yes, sometimes, in the course of a prolonged home visit. Or we send them to others with more time. Here is a superb practical guide on how to do it.

Arch Intern Med  Vol 171
Last week the journals reached a new low in volume of worthwhile content, but this week they have broken the record again. To keep you going, here are a few morsels from the Archives website:

For thousands of years, doctors have loved taking blood. Even William Osler retained a vestigial folk-belief in the benefit of phlebotomy for pneumonia, well into the twentieth century. When the moon is full, doctors are particularly dangerous and sometimes grow hair in unusual places. In teaching hospitals especially, young doctors partake in vampiric initiation rites which involve the filling of innumerable tubes of blood in pursuit of ever more improbable diagnoses. Following such youngsters round a prestigious American hospital recently, after many years in British general practice, I found this mildly amusing: but I learn from this paper that it can actually do harm to patients with acute myocardial infarction in Kansas. Believe it or not, quantities of blood as small as 180ml can make a difference to the incidence of post-MI unexplained anaemia, which in turn can worsen outcomes. The severity of this anaemia seems to correlate well with the amount of blood removed: some particularly hungry doctors take more than 300ml. As the authors of this study note, we could all let our patients retain their rightful lifeblood if we simply used paediatric tubes. But stay! what is that distant howling in the moonlight?

Now the Archives are supposed to be the B-journal for JAMA, which is a pretty impossible feat at the moment. This Italian study of radiography at home is definitely B-level stuff but hey, it is from Italy, and also interesting. Show respect. They took modern lightweight X-ray machines out to frail old Italians and proved (well, actually, claim from a single descriptive case series) that X-rays done at home are just as interpretable as those taken in hospital; and also this spares the patient the horrors of admission, especially delirium. Moreover, “almost all patients” were satisfied. I would love to hear what was said by the patients who weren’t.

Plant of the Week: Diospyros virginiana

This lovely East American tree is the origin of our word “persimmon,” as Eric Larson explains below. I came across one in its native Virginia on the slopes of a fort guarding the Potomac River, where its fruits lay on the ground and attracted the sporadic attention of local marmots. I guess this is yet another American plant that you could, in theory, grow in England, but never to much effect. If you wanted to taste its sweet golden fruit, you would have to plant it where the sun beat down upon it for three months with hardly any interruption.

The persimmon we buy in the shops comes from a much-hybridized Far Eastern species, Diospyros kaki. But the original lotus-fruit comes from Diospyros lotos, widely grown around the Mediterranean, and my favourite guess for the forbidden fruit of the Tree of Knowledge in the Garden of Eden,
                   ….whose mortal taste
Brought Death into the world, and all our woe.

I will let Eric Larson, keeper of the Yale Botanical Gardens, take over:

Persimmon (Diospyros species)
by Eric Larson

Persimmon is one of those very misunderstood edible items, like brussel sprouts. If you have ever partaken of a Persimmon fruit when it wasn’t “dead ripe,” then your impression will be one of astringency, sourness, even discomfort. One of the tricks that I learned from my beloved sister and her husband is to place the persimmon in the freezer overnight. After taking it out and thawing it, all astringency is removed and the true sweetness of the fruit will remind us of why the Greeks considered it the “fruit of the gods.”

In fact, the genus name is Greek: dios of Zeus (later Jove) and pyros for grain, alluding to the edible fruits. The common name actually comes from the Powhatan (an Algonquian language) word for the fruit: depending on the written translation putchamin, pasiminan, or pessamin. The family is Ebenaceae, the Ebony family which includes five hundred species in two genera, Diospyros and Euclea, the genus for Ebony trees.

Diospyros virginiana is an American native persimmon, which one would guess if the Algonquin had a word for it. But persimmons are distributed world wide. The Far Eastern species provide the greatest reliability of ripeness and taste, and have been selected and perhaps hybridized for countless generations. The most widely cultivated species, D. kaki, is called kaki in Japan, shiziz in Chinese. China, Korea, and Japan make up the largest part of the worldwide production of persimmon.

Two basic types of Persimmon fruit: astringent and non-astringent.

There are varieties of almost every species that fall into each category.  I’m not sure why this should be in an evolutionary sense. Perhaps something to do with offspring dispersal. Perhaps, like humans, there are astringent sourpusses and then happy-go-lucky folks. As I said earlier, freezing releases astringency, breaking down the cell walls and allowing the tannin to be solubalized into the sugar solutions. Non-astringent fruit can be eaten when firm, without freezing, and therefore are considered a delicacy. There are other ways to achieve the same result as freezing, including using alcohol and carbon dioxide in what is called a “bletting” process. My advice is: go ahead and freeze the fruit.

Another historical/literary note: the species native to southeastern Europe and western Asia, D. lotus, is referred to in several languages as “date-plum,” because its taste and texture are reminiscent of both of those fruits. This species is thought by some to be the fruit referred to as “the lotus” in the Odyssey: it was so exquisite in flavor and nutrition that it made those who ate it forget about returning home, wanting to stay and eat lotus with the lotus-eaters.

Nutritionally, Persimmons are high in vitamin C (the American native is the highest in this regard), and other nutrients, but also have tannins in the form of catechin and gallocatechin, and anti-tumor compounds betulinic acid and shibuol, the latter which may cause some intestinal discomfort. As a matter of fact, my tummy is feeling a bit “off” right now after having eaten two small ones. No real problem, just a slight “eh.”  It is said that they should not be eaten with crab-meat nor eaten on an empty stomach. Well there goes my favorite breakfast, crab and persimmon omelette.

The trees themselves are small, depending on the species.  They grow from twenty to forty feet depending on where they are located.  They will grow in light shade to full sun, with full sun best for flowering and fruit production.  The American species or those crosses that have some of that parentage are the most cold-hardy for us. The kaki and other types are more tender.  They leaf out very late in spring, making one think that the winter might have got them. Be patient though. They flower well after leafing out, which makes them a good candidate for those areas with late spring frosts.  The fruit doesn’t form until very late, and on the American species they aren’t ripe until after the leaves drop in the fall.

The fall color is a nice yellow, sometimes orange. They are very adaptable as to soils, tolerating flooding conditions or droughty sandy soils. I would advise you to look into persimmons as an alternative to the fruits that need so much spraying that are subject to disease and insect problems.  They are available through mail order and sometimes in the better nurseries.

JAMA  24-31 Aug 2011  Vol 306
840   Every GP knows that some patients who are admitted to hospital come out without their usual medication and take this as an indication that they don’t need it any more. This happens particularly after admission to ICU. The team doing this cohort study in Ontario makes an attempt at quantifying what effect this might have in terms of death plus readmission: nothing reaches statistical significance but it’s interesting to note the tendency towards harm from stopping statins and aspirin and the tendency to benefit from stopping respiratory inhalers in this largely elderly group with chronic illness. Somebody needs to repeat this natural experiment as a properly powered RCT by taking all older patients with comorbidities off their steroid, beta-adrenergic and anticholinergic inhalers and replacing them with identical-looking placebos and looking at mortality and hospital admission. Or maybe we’re already past the point of equipoise – we already know that these puffers increase rates of infection and total mortality for most adult groups; and yet we carry on prescribing them by the bagful.

856   It’s amazing what happens in diastole: valves open and shut and oxygenated blood floods into the left ventricle and the coronary arteries, while the right heart fills with venous blood from the rest of the body. Then in half a second or less it all goes into reverse. Arterial blood pressure zooms down and then back up again, creating a characteristic pressure wave which is modified by the elasticity of the arterial wall in the greater part of the arterial tree. Gradual stiffening of the heart and the arteries can lead to heart failure with preserved systolic function: this is not synonymous with diastolic dysfunction though the two often go together. To fully understand why so many old people – especially women and people with diabetes – slowly develop this kind of “heart failure” you would need to do long-term sequential measurements of their pulse pressure, their arterial elasticity, their levels of natriuretic peptide, their coronary perfusion and their indices of diastolic LV filling on echocardiography. I once thought of doing such a study but concluded that it would be of little benefit: by the time you have heart failure, your heart is failing. This cohort study from Olmsed County just looks at the cardiac events in diastole and concludes that an early restrictive filling pattern does herald deteriorating function and the development of overt failure over 4 years.

NEJM  25 Aug 2011  Vol 365
689   In the days before chronic obstructive pulmonary disease existed, we used to call it chronic bronchitis and would often treat it with continuous antibiotics through the winter months. But from about 1980 onwards, such primitive strategies were increasingly frowned upon, and instead these unfortunate victims of smoking were given all sorts of beta-stimulants, theophylline derivatives, inhaled steroids and inhaled anticholinergics, as noted above. Now we have come full circle with a trial of daily azithromycin for 12 months in addition to usual care for COPD. This reduced exacerbations by a quarter and improved quality of life. As the authors note, we don’t know what effect such a strategy, widely employed, would have on patterns of respiratory bacterial resistance. But I think the greatest benefactors to pulmonology (as it is called over here) will be the people who invent new antibiotics – though the old ones are still good enough for most purposes – and new ways to help people stop smoking.

699   Apixaban is a coming drug. You know what it does – come on, think. Xa-ban: it blocks Factor Xa, it’s oral, and it’s fixed dose. So one day soon you will be prescribing it instead of warfarin. But it does make people bleed, of course, especially when combined with an anti-platelet drug. The APPRAISE-2 trial was designed and sponsored by Bristol-Myers Squibb and Pfizer in the hope that it would reduce recurrent ischaemic events if given after acute coronary syndromes together with aspirin or clopidogrel: but it didn’t, and the trial was stopped early due to the increase in major bleeds. Not that B-M S and Pfizer will mind all that much: this drug and the other xabans (and also the direct thrombin inhibitors) all have an enormous potential market already.

Lancet  27 Aug 2011  Vol 378
771   It’s old news, but it’s good news: tamoxifen given for 5 years for oestrogen receptor positive breast cancer in postmenopausal women reduces recurrence by one third. This is the very robust conclusion of an updated meta-analysis of 20 randomized controlled trials. Overall non-breast-cancer mortality was little affected, so this drug has saved a lot of lives.

785   Biochemical screening in the newborn is generally such a success that nobody questions it; even me. And we all diligently carry out physical examination of the newborn at 48hrs and 6 weeks; even me. But despite these examinations and routine antenatal ultrasound for cardiac defects, a lot of time-critical congenital heart disease still gets missed. This Birmingham trial looks at whether we could do better by using routine pulse oximetry for the newborn, taking oxygen saturation measurements at the hand and the foot. To me, a screening sceptic, this paper makes a good case for universal pulse oximetry screening. I am surprised the accompanying editorial isn’t more enthusiastic. In study conditions, the sensitivity was 99% and testing also detected other kinds of critical illness in 40 out of 20,000 tiny new babies.

BMJ  27 Aug 2011  Vol 343
Actually there is no print issue of the BMJ bearing this date, but to flesh out what is an exceptionally lean week, I’ll talk about two papers which have just appeared on the website.

All doctors have a slightly uneasy relationship with prognosis in cancer: it’s hard to break bad news, and most of the time we are wrong if we attempt even the vaguest time frame. There is a strong movement within palliative care which argues against prognostication on the grounds that it is a distraction: the message this movement promotes is that if you wouldn’t be surprised if the patient died in the next year, you should call in palliative care. All very well, but how do you put that to the patient, especially if the diagnosis is not cancer? But I digress: the patients in this study did have cancer, and the investigators sought an “objective” set of criteria to predict death within days, weeks, or months, which would be better than the judgement of individual clinicians. They claim to have done this here, with quite complex instruments, one of which incorporates blood tests. They’re still wrong 40% of the time.

A fascinating study of the types and progression of headache over 30 years among the worthy burghers of Zurich. It was while looking across the many clocks of the city that Albert Einstein first conceived the notion that time could be relative rather than absolute. Now if I had an idea of such grandeur I would inevitably pay for it with a migraine with aura, as I get these with great frequency (though not great severity) whenever I exert myself mentally – and of course hardly a day goes by without my reformulating the basic laws of the Universe. It’s actually relatively uncommon for a man to get migraines with aura and to keep them for life. Only 20% of people who get migraines keep on getting them for more than a few years, and most of them are without aura and occur in women. People’s headaches tend to vary through life, at least in Zurich – a place, one would have thought, as free from anxiety as any on earth.

Plant of the Week: Albizia julibrissin

I remember being seized with a desire for this plant many years ago, when I caught sight of it in a book on trees and shrubs designed to straddle the British and American markets. Now such straddling can often be cheating: I don’t think there can be any two places in the UK and the USA which have truly similar weather conditions. American seasons follow a continental pattern, even on the sea coasts. Summer is hot and sunny; winter is cold and snowy. You know where you stand.

Now the silk-tree, which comes from Iran, is a plant that likes to stand in hot sunshine for several months of the year. Then it will be perfectly ready to stand in frost and snow for the other half. It has lovely ferny pinnate leaves and the most beautiful and unusual tufts of pink silk for flowers – hence its common name. It bears itself graciously and is covered with flower in New Haven CT from early July to late August and looks set to carry on. Whether it ever flowers in the UK I am unable to say. It is certainly offered for sale in English nurseries, but I suspect the only time you will see the silken tufts is on the plant label, and perhaps during an occasional freak British summer featuring prolonged warmth and sunshine.

This small tree gets its bizarre name from the Italian nobleman Filippo degli Albizzi, who first introduced the Persian species to Europe, and from the Farsi gul-i-abrisham, meaning flower of silk. I have only seen a walled garden in Iran during the winter months, so I don’t know if the gul-i-abrisham flowers there: I imagine so, among the cypresses, almonds and pistachios and neat terraces of bedding plants grown along carefully maintained water-courses. A place of this sort was known in ancient eastern Iran as pairi.daêza and associated with the Zoroastrian heaven, or Place of Song. The word has come down to us as paradise.

JAMA  17 Aug 2011  Vol 306
711   Randomized controlled trials of new interventions have become something of a rarity in JAMA of late, so I was interested to see this account of two industry-funded trials of pegloticase, a genetically engineered uricase designed to lower uric acid in people with treatment-resistant gout. This drug already has FDA approval, presumably because they were convinced that it might be of benefit to a proportion of the 3% of gout sufferers who don’t respond to other methods of uric acid reduction. The small trials described here were done in 2006 and 2007 and they reveal that pegloticase lowers uric acid in fewer than half of these patients and doubles gout attacks in the first six months of treatment: we don’t know what happens beyond that. Infusion reactions were common and nearly all the patients developed antibodies to pegloticase, sufficient to neutralise any benefit in over a third of treated patients within the six month trial period. A pretty lousy drug by any standards, with unknown long term effects, and available to all Americans now thanks to Savient Pharmaceuticals and the FDA.

754   Medicine can’t go on the way it is – every thinking person agrees on that, especially in the USA, which manages to combine massive health expenditure with dismal hard outcomes. Yet in the face of the world economic crisis and global overpopulation, we go on doing more of the same. In my home university of Oxford, for example, the Regius professor called last week for a much bigger focus on genomic research, while the Clinical Trials Support Unit has taken a huge grant from pharma to run a trial of yet another lipid-lowering agent. But what the world needs is a vision of patient-centred medicine based on hard outcomes, and this is what Harlan Krumholz sets out here. This short piece – real world imperative of outcomes research – is a must-read for anyone who cares about the future of medicine.

756   The chief agency for change in the USA should be a new body called the patient centered outcomes research institute, but at the moment it lacks a clear agenda. This piece is about the challenges it faces, and it illustrates the problems all too well. It lacks focus and meanders from a general discussion of bench-to-bedside research to a specific complaint that doctors don’t prescribe enough thiazides for hypertension following ALLHAT. Hang on, what has all this to do with patient centred outcomes research? That’s not about benches, it’s not even about bedsides, it’s above all about free living individuals making rational choices about their treatment based on the outcomes that matter most to them.

762   This New Medicine, based on patient important outcomes, is not going to be easy. I am trying to compile a book about it with four keen young doctors and the problems and the gaps are huge. This editorial focuses on the mismatch between variations in processes of hospital care (Medicare’s 25 process metrics) and outcomes of care. If you look at enough hospitals, both tend to have a normal (Gaussian) distribution, but with rather poor correlation between the two bell-curves. And then there is cost…

NEJM  18 Aug 2011  Vol 365
591   Intra-operative awareness during anaesthesia is a rare but terrifying prospect, like being buried alive. As a friend has written, the idea of having to lie there helplessly and listen to several hours of surgical banter is enough to put anyone off ever having an operation. One theory was that this is due to some patients having a blunted response to anaesthetic agents, but this trial effectively rules that out. Awareness during anaesthesia correlated less with changes on an encephalogram than with measured end-tidal anaesthetic gas concentration. Give them enough gas and they’ll stay asleep.

601   It’s deepest mid-August and so what tends to be put out in the journals is peanuts. The role of the humble ground-nut in American civilization may have diminished somewhat since it peaked in the peanut-butter-and-jelly heyday of the 1950s, but contaminated peanuts still have the power to poison large swathes of the US population. A single peanut- crunching factory caused an outbreak of Salmonella typhimurium disease across 46 states from sea to shining sea – all carefully described in this paper, a classic in the archives of detective epidemiology.

Lancet  20 Aug 2011  Vol 378
667   This week’s Lancet is devoted largely to heart failure, described in the opening editorial as a “dangerous, debilitating, and common disease, subjecting patients, carers, and doctors to a substantial burden.” But really CHF is not a “disease” but the final common pathway of a number of diseases, a pathway that leads inevitably to death. A patient-centred view of heart failure will therefore take account of the patient’s desire to stay alive or to lead a more tolerable life, and the trade-offs between the two. It has been known for over ten years that most patients with HF, being over 70, value quality of life over quantity*; yet very little HF research reports on symptomatic benefit rather than mortality and rehospitalization, despite the existence of at least 5 well-validated symptom scores. All this is just a preamble to two studies of a new inotrope for heart failure, omecamtiv mecarbil. This has a fascinating new mode of action on the actin-myosin interaction of the cardiac myocytes, and I wish it well. These studies were not designed to assess its clinical benefits, just its safety and dose range. It will never be used in the community, because it has to be given intravenously. But if it is the precursor to oral drugs that make people with heart failure feel better while shortening their lives (like all previous inotropes), then this is a valuable advance, and just what many HF patients would like to choose.

*in fact that has been known in general for over 3,000 years: see Psalm 90 (attrib Moses):
10. The days of our years are three-score years and ten: and if by reason of strength they be fourscore years, yet is their strength labour and sorrow: for it is soon cut off, and we fly away.

684   I do wish I didn’t have to report on this study called MESA, which alludes to another study called JUPITER, because it treads on all my corns. High-sensitivity CRP is a useful new predictor of cardiovascular risk, right? No, no! – it is neither new nor usefully predictive. We need better ways of determining which people should be given statin therapy for life, right? No, no! Statins are cheap and beneficial and if they give people muscle pains, they can be stopped. So we should use coronary artery calcium measurement by CT scanning to determine which people don’t need to take statins, right? No, no! Because you will be using huge amounts of money and radiation, and generating population-wide anxiety, all in order to save about 10% of the target population from taking a cheap and harmless drug. Now go away.

704   Four reviews of heart failure topics now ensue. They aren’t all that good, and the last, on telemonitoring in HF, simply flies in the face of the evidence. The first one deals with advances in basic science. I don’t wish to decry this work though I don’t suggest that anyone but a superspecialist should read this paper. The bench-to-bedside model will work this way: a new pathway will be elucidated (3-5 years); a drug which enhances or blocks this will be developed and tried on an animal model (3 years); Phase 1 and 2 human trials will follow (2 years); then clinical phase 3 trials (5-8 years) on patients with heart failure, mostly male with reduced EF, lying in Veterans hospitals and already on four different HF drugs. Some tiny benefit in a composite outcome of death and rehospitalisation may or may not result; if the trial is quite exceptional, it may use some patient-reported outcome measures too. I dare say we need this kind of research, but we so much more urgently need research on what helps make living and dying with HF more tolerable for our patients here and now.

BMJ  20 Aug 2011  Vol 343
More about outcomes research, I fear: I fully intend to become a bore on the subject. Surgeons were among the first to report on their outcomes (as individual case-series), and as far back as 1913, Ernest Codman was calling for the public reporting of end-results of surgical procedures in hospitals. We are still learning how to do it. Here no less a surgeon than Lord Darzi himself has a go at analysing variation in reoperation after colorectal surgery in England as an indicator of surgical performance. Our one-time czar and master is surprised at how much variation there is and how little of it correlates with procedure volume: 

“Even at a high caseload, however, there was substantial variation in both the trust (hospital) and surgeon team reoperation rates. There was a fivefold difference in highest and lowest reoperation rates after elective surgery (14.9% v 2.8%) among the surgical teams performing >500 procedures. There was a threefold difference in reoperation rates in trusts performing >2500 procedures during the study period (11.5% v 3.7%).”

Bell-shaped plots again. And how rarely complex systems behave simply. Welcome to our world, Dear Leader.

Ann Intern Med  16 Aug 2011  Vol 155
217   The encouragement of good clinical research in China is vital for the progress of medicine, and it’s even possible that Chinese traditional remedies might yield occasional useful discoveries. Artemisia annua for malaria is an often cited example, though in fact the Chinese used it for almost everything except malaria. Maxingshigan–yinqiaosan, as some readers may know, is a popular Chinese remedy for influenza. The popular Western remedy is oseltamivir. This trial compares one with the other or with both or nothing, and the primary end-point is time to fever resolution in laboratory-confirmed H1N1 influenza. So far so good. It’s mildly interesting that maxingshigan–yinqiaosan and oseltamivir achieved about the same 19% reduction in fever time and had made no difference to symptom scores, i.e. these are clinically useless interventions with barely detectable antipyretic effects. But if Chinese RCTs are to get into reputable journals, they really should go in for a bit of double-blinding. This one wasn’t even single-blinded.

Fungus of the Week: Lepiota procera

The true field parasol mushroom is beautiful to look at and delicious to eat, but I’ve had decidedly little luck finding any in Europe over the last 35 years. In fact the nearest I’ve come was in the covered market at Krakόw where there were piles of parasol caps about 15cm across, commanding higher prices than the neighbouring heaps of Boletus edulis. However, I have just found a couple growing by a sandy path in Connecticut.

The cap of this delicacy looks just like a parasol of pale creamy brown with darker ring-like ridges. These are even more marked in its cousin, the shaggy parasol. However, if you break open the flesh of the field parasol it remains white or very pale buff while the flesh of the shaggy parasol slowly turns bright orange. This is important because the field parasol is universally edible while the shaggy parasol can cause gastric upsets, despite tasting just as delicious. I can vouch for this, though in my case the upset tends to occur a little further down the intestinal tract.

These two large lepiotas are the only edible species to grow in Northern Europe. You can easily tell them from amanitas because their stems are thinner, taller, and tougher: also if you wobble the veil remnant about, it will move free of the stem. It is such a shame that nobody has worked out a way of growing them commercially.

Arch Intern Med  8/22 Aug 2011  Vol 171
The order in which I place these journals does not reflect merit, but dates back to 1998 when I first made some experimental one-line notes on the journals as they arrived in the post. O happy days! There was something good about handling the paper copy, and the cover of JAMA was generally beautiful and interesting, and its contents were generally good too. But now JAMA lies pale and moribund, awaiting the kiss of Prince Charming or the electrodes of Baron Frankenstein. People assure me that Howard Bauchner, the newly appointed editor, is more likely to resemble the former. But while he performs CPR on what is supposed to be the AMA’s flagship journal, the lower-rated Archives are far superior and fizzing with life under the charge of Rita Redberg:

1322   I used to love new diagnostic chemicals. Fancy being able to take some blood and know with complete certainty that someone had coeliac disease (endomysial antibody) or myocardial infarction (troponins)! So each time a promising new test came up, I wanted to do some primary care studies. Procalcitonin appeared in the literature about 8 years ago and I immediately wanted to design a study with some Oxford colleagues, but the evidence of its value for discriminating between bacterial and non-bacterial infection was then too sparse. Others have since done primary care studies of lower respiratory infection and studies have also been performed in emergency departments and in intensive care units. They are usefully assessed in this systematic review: it seems that procalcitonin-guided antibiotic prescribing reduces antibiotic use without affecting mortality. There is plenty of scope for bigger, better studies in the context of acute primary care e.g. in out-of-hours centres. But I fear that this approach will never be widely adopted until the cost of a near-patient test approximates to the cost of a week’s course of amoxicillin.

1344   All the time I spend in the USA, I am trying to understand their health system and how its lessons might apply to ours, and vice versa. Tiring work. Throughout the UK, people of my age upwards are being sent little packages so they can test their stools for occult blood. I threw mine away. This paper describes what happened to 212 people over the age of 70 (no, I’m nowhere near that) who tested positive for faecal occult blood. Only 56% of these had a follow-on colonoscopy, and of these, 10% had serious adverse effects due to the investigation or due to treatment for cancer. The 43% (94 people) who weren’t followed up properly included 3 people who died from bowel cancer in the next 5 years and 43 who died of other causes. The greatest “burden” from this screening process seemed to fall on those with the lowest life expectancy. I don’t know what lessons this has for the NHS. It certainly shows that without a robust system of follow-up, you’ll miss some cancers. But it also confirms my feeling that FOB testing is a lousy way to screen for bowel cancer, likely to overwhelm diagnostic resources and possibly do more harm than good.

1363   Soy Isoflavones in the Prevention of Menopausal Bone Loss and Menopausal Symptoms: a Randomized Double-blind Trial. There are two schools of thought about RCTs: that we need to do lots more with increasing power to detect small effects; or that we already do too many and they are often far too big because if an effect is clinically important, it will be obvious with small numbers. I am firmly of the latter school. This RCT was not really needed, because we already know that soy products do nothing for menopausal symptoms or osteoporosis. Had it been run by a soy product manufacturer, maybe they would have recruited thousands of women in hundreds of centres and found some subgroup effects of borderline statistical significance. Then they could have lobbied the licensing agencies hard until they conceded the right for doctors to prescribe this stuff to half the female population over 50. But the soy product manufacturers sell cartloads of their junk over the counter already, and a small (n=248) one-centre government-funded RCT was perfectly adequate to test clinical significance. I don’t suppose it will make the slightest difference to the “phyto-oestrogen” market.

1371   We should all be grateful for the existence of nephrologists: doctors who can work night and day measuring people’s bicarbonate, creatinine, and electrolytes, providing dialysis, and offering ready advice to ignorant colleagues and well trained patients. In the UK, there are probably too few of them, and if we send them patients who aren’t likely to need dialysis soon, they send them back to us until their creatinine gets to 300 nmol/L or beyond. Of course, their professional societies say that we should be sending them patients sooner: but this is rot. This study shows that in the USA, patients are seeing nephrologists sooner and being put on dialysis earlier, but that 1-year survival after dialysis has not improved. The implication would seem to be that patients actually die sooner if their dialysis is started earlier. Nephrology, it seems, can be dangerous.

JAMA  10 Aug 2011  Vol 306
587    The Poetry and Medicine section of JAMA has a cult following: it’s perhaps the most reliable source of bad verse in the world – toe-curling, emetic, and hilarious by turns. It says a lot about the present state of JAMA that this week’s poem is about the best thing in the journal. It’s really quite good, though I can’t link you to it unless you have a JAMA subscription. The title is Number Needed to Treat, and I can give you its last line, because this at any rate can’t infringe copyright:
eeny meeny miney moe.

613   Some years ago I read a study which showed that sleep apnoea could be diagnosed as reliably by taking a history from the sleep partner (when available) as by all the usual sleep clinic technology. In this study of sleep-disordered breathing in older women they were taking no chances: “Channels included 2 central electroencephalograms, bilateral electrooculogram, chin electromyogram, thoracic and abdominal respiratory effort, airflow (using nasal-oral thermocouple and nasal pressure recording), finger pulse oximetry, electrocardiogram, body position, and bilateral piezoelectric sensors to detect leg movements.” What they demonstrate here is that only sleep-disordered breathing that causes hypoxia is associated with cognitive impairment in women. The same almost certainly applies to men.

NEJM  11 Aug 2011  Vol 365
Well into the second decade of the twentieth century, I guess it is time for me to bow to the inevitable and start reviewing papers as they appear on journal websites rather than in the printed journals.

The big excitement on the NEJM website this week is the ROCKET-AF trial showing that rivaroxaban is as good as warfarin in preventing stroke and peripheral embolism in older people with non-valvular atrial fibrillation. This was a well-conducted trial which went to considerable lengths to achieve double-blindedness despite the need to provide sham INR values for those on rivaroxaban and real ones for those on warfarin. The standard of reporting is good, except for various switches between intention-to-treat analysis and as-treated analysis, which are unnecessary and confusing. However you cut the data, rivaroxaban is at least as good as warfarin, when only 60% of patients are within the target INR range. That was the mean for the 45 countries that took part, though much better control can be achieved in an efficient system. Still, if I were a patient, I’d much rather have a fixed-dose oral drug than one which requires blood tests and dose changes: and this will certainly come one day soon. In the meantime, Johnson & Johnson and Bayer made sure they ran a good marketing trial, recruiting 12 patients on average from 1178 centres around the world.

493   A superb 9 country study establishes that early retroviral therapy prevents HIV transmission between infected and non-infected stable partners (97% heterosexual, 94% married; equal numbers of infected women and men). The logistics of this study compel wonder and its findings will change practice.

527   And now for the longest running quest in pharmacology – the search for a perfect laxative. My hunch is that it began in the Jurassic period, when carnivorous dinosaurs who got bunged up might have eaten fern shoots in imitation of their huge belching and farting vegetarian cousins. Certainly laxative-seeking behaviour is widespread among mammals – the bear wakes from hibernation to tear at birch bark and lick the sap which will release its anal plug; the costive cat eats grass. The earliest human records list rhubarb, liquorice, and other herbs and barks. Linaclotide may be the Holy Grail of this 100 million-year quest, though the two trials in adults with chronic constipation reported here are somewhat underwhelming: at best just 20% found success at the Stool of Easement.

Lancet  13 Aug 2011  Vol 378
The printed Lancet makes for rather lazy browsing this week – there’s a global survey of hepatitis B & C in IV drug users, a whole cavern of gene gnomes talking about the MTHFR genotype and folate metabolism, and a vaguely promising drug for Duchenne muscular dystrophy achieves favourable changes in muscle biopsies in 7 out of 19 subjects.

Richard Horton in Offline moves from Norway to Brazil, where at the end someone appears to have slipped some mescaline into his nightcap:

“If the health system is to solve its puzzles, there must be an awakening about our relations, one with another. The interdependence we share. Our communion of purpose. It will win elections.”

The Lancet website is chiefly notable for a meta-analysis on the effect of cigarette smoking on coronary heart disease in women compared with men. The evidence swings both ways but the most likely conclusion is that women are 25% more likely to suffer coronary events than men for any given level of smoking.

Then my attention was caught by an article that I nearly overlooked in the paper version:

621  Novel melatonin-based therapies: potential advances in the treatment of major depression. With SSRIs falling out of favour, we badly need a new class of antidepressants, especially if they help people relax and sleep better. Or do we? Are we perhaps just in for a further round of wishful, circular thinking about “major depression” and the brain biochemistry which underlies it, or results from it, or merely coexists with it. High quality medical journals have a responsibility to give us reliable and impartial information and guidance about such things. So how does this contribution shape up? Well, it goes through a range of melatonin derivatives and concludes that:
“Importantly, only agomelatine (which also binds 5-HT2C receptors) has been reported to have clinically significant antidepressant effects. Because of its favourable adverse effect and safety profile, and the potential to help to restore circadian function between depressive episodes, this drug might occupy a unique place in the management of some patients with severe depression and other major mood disorders.” Ahem, is there anything we should know about the authors possible conflicts of interest in relation to the manufacturer of agomelatine, Servier? There certainly is. It defies belief that a reputable journal should commission an ostensibly impartial review of an important area from two authors who have both received grants from this same drug manufacturer.

BMJ  13 Aug 2011  Vol 343
Conflicts of interest are the subject of a splendidly forthright editorial by Fiona Godlee – in this case relating to the workings of the US Food and Drug Administration and its even more pusillanimous transatlantic equivalent, the European Medicines Agency. Our guardians and watchdogs would like to loosen a system which already allows manufacturers to massage and withhold data at will. How many patients – indeed how many doctors – realize that half the trials on the drugs and devices they use are locked away in company files and have never been subject to independent scrutiny?

Putting genomics into practice: now there’s a title to make you sigh. I clicked on this editorial expecting to read the usual hyped-up waffle and special pleading: but this is just the opposite. It’s a beautifully realistic and well-written piece which even contains a useful alternative to the much-misused term “personalised medicine” : stratified medicine more accurately describes the sort which may one day be possible when we feed in the patient’s genome card into the computer and decide to prescribe them drug B instead of drug X. Personalised medicine will remain what it is now – talking to them about their mother’s death, telling them that they can eat what they like, sharing a joke.

Even the prescribing of drug B rather than X often lies beyond modern genomics, despite the discovery of plausible gene loci. Variants at the CYP2C19 locus should by rights determine the clinical efficacy of antiplatelet treatment with clopidogrel, but this systematic review shows that they don’t to any meaningful degree.

The management of febrile illness in adolescents and adults in resource-poor settings is clearly a topic of major global importance and it gets a very good Clinical Review here. The only problem is that doctors in resource-poor areas won’t be able to access it without a BMJ subscription. Surely this is an oversight that needs correction.

Plant of the Week: Franklinia alatamaha

Here is an account of this quintessentially American plant by Eric Larson, Keeper of the Botanical Gardens at Yale, written in August 2005:

Our Plant of the Week is Franklinia altamaha, or the Franklin Tree. The common name and genus name are for Ben Franklin, friend to the botanist who discovered the small flowering tree on the banks of Altamaha River in Georgia. John Bartram found this plant in 1770, during his travels through the southeastern part of what would become the United States. John’s son William also traveled extensively through that same area, only his journal writing was much more advanced,
which resulted in Bartram’s Travels, said to be “one of the most astounding verbal artifacts of the early republic.” I highly recommend the book to you.
 
This plant is no longer growing in the wild. In fact, since 1790, there have been no sightings of Franklinia in its habitat. John Bartram brought back a number of specimens, and it is from these that all of today’s plants have descended.

Franklinia belongs to the Tea family, Theaceae, which also includes Camellia and Stewartia. Franklinia grows to about twenty feet high, by fifteen feet across. The national champion is thirtyseven feet tall. The small stature makes it an ideal plant for the home garden. The fact that it sets big white fragrant blossoms in July, August, September and even into October doesn’t hurt its chances for inclusion in any landscape. Add in the fact that it often has spectacular fall foliage, and you have a real knock out for the front yard.

Best planted in spring as a balled-and-burlapped youngster (be sure, again, not to buy too large a specimen: harder to handle, more expensive, more transplant shock, etc.), in full sun or light shade in a moist, acid but well-drained soil. Think of a sandy bank on a river in Georgia to replicate for this plant. Ours is growing next to the spring that fuels our wetlands area. It is quite hardy here in New Haven, and available at the better local nurseries.

………………………………………………………………………………………………
Eric introduced us to this plant yesterday. It has grown beautifully in the last six years and bids fair to outclass the national champion.

I don’t have my copy of Bean’s Trees and Shrubs Hardy in the British Isles handy with me here, but my guess is that dear Bean will say something like “our climate does not appear to suit it, and it is seldom seen to flower even in our warmer counties. A specimen at Nymans reached 16ft 5in before it succumbed to the damp winter of 1935.” Here in New Haven the winters are long and freezing but the summers are hot and humid. If you have a sandy acid garden and a disposition of unquenchable patience and optimism, I could send you some seed from Yale. Or else you could buy a small plant from one of six British nurseries listed in the Plant Finder.

JAMA  3 Aug 2011  Vol 306
493    This issue of JAMA is devoted to war and violence, things that most of us have not experienced. Those who do experience them, like most of the population of Europe in the generation before mine, are never unscathed. The study here discovers that military veterans with post-traumatic stress unresponsive to antidepressants do not respond to the addition of risperidone. No surprise there: they are just the extreme end of a spectrum of people who seldom respond to treatment but mostly respond to time. Looking at table 1, it seems that three quarters of these veterans had not seen battle for over 40 years: and an unspecified number are listed as having fought in WW1, which would make this the first published trial of a posthumous intervention. More typically, it took men who fought in that war about ten years to recover any feeling of normal life; such at any rate was the case with the Great War’s greatest writer, Ford Madox Ford. You don’t believe me? Read Parade’s End and No Enemy.
NEJM  4 Aug 2011  Vol 365
395    Reducing mortality from lung cancer is a worthy aim, which we all pursue as best we can while governments draw billions of pounds from tobacco revenues. What is the place of screening in all this? Here are the results of the National Lung Screening Trial (NLST) which shows that compared with annual chest X-ray, low dose helical computed tomography done for 3 consecutive years in people at high risk can reduce lung cancer mortality by 20% at six years. An editorial by Harold C Sox, attempts to place this in the context of previous trials, and the authors themselves give a very cautious and thoughtful appraisal of their success in the discussion section of their paper. The false-positive rate for CT in this group was very high (23%), but led to surprisingly few invasive tests and very little mortality in contrast to earlier trials. The benefit in overall mortality seems significant and not entirely due to lead-time bias and other kinds of confounding. But the analysis of screening studies is a complex art: if you want a highly readable introduction to it, go to Overdiagnosed (Beacon Press, 2011) by Gilbert Welch, Lisa Schwartz and Steven Woloshin. Then pore over the figures and charts in this paper and see if you can form your own opinion. And then think of the whole picture: in the context of a cost-effective health service, is this something we should start rolling out?

439    Chronic hypertension in pregnancy gets a rather generalised review here – the “chronic” is there to distinguish it from acute pre-eclamptic toxaemia, though of course it is itself a risk factor for PET. There is a useful table of blood pressure lowering drugs which are safe to use in pregnancy. Hypertension in women of child-bearing age is not common and needs investigation, in my view preferably with measurement of renin and aldosterone under controlled conditions: but the article does not go into this but simply suggests following the JCN 7 guidelines in those on multiple drug therapy. If you want to know what these guidelines are, a reference is given. For an old man like me, the rate at which Americans throw out initials and acronyms is a cause of despair. Did I hear that right? Am I cognitively impaired? There is no need to answer these questions.

Lancet  6 Aug 2011  Vol 378
487   For the third week running, we get a negative trial of a new intervention for type 1 diabetes. It is a gloomy sight: most of the beta-cells lie slain or dying on the autoimmune battlefield. Researchers seem to be seized with the desire to fight back and protect the few remaining cells, even though the war is effectively over. The manufacturers of teplizumab are no exception, and the Lancet allows them to report this trial as full of promise, though it was a complete flop. Teplizumab when given within 12 weeks of the diagnosis of T1DM made absolutely no difference to sugar levels or insulin requirements. It interferes with some aspects of T cell function and complement binding, and keeps beta-cells alive longer, as shown by maintained C-peptide levels at 12 months. In an editorial called “Anti-CD3 antibodies for type 1 diabetes: beyond expectations,” Jean-François Bach’s imagination takes flight: “Ideally, type 1 diabetes should be regarded as a medical emergency and treatment with teplizumab could be started within a few days after diagnosis, as compared with several weeks or months as is done now.” The basis of this statement is a post-hoc analysis of a small subgroup at the highest dosage who showed the highest C-peptide response. Is there no such thing in diabetes as waiting for some evidence, preferably of benefit to patients?

507   In a review some years ago, I read that every mammal has its own species of Helicobacter and that in most cases these bacteria behave more like commensals than pathogens. The implication is that before the antibiotic era, every human carried H pylori, and that by trying to eradicate it, we are carrying out a huge (un)natural experiment. Of course, these ancient and resourceful spirochaetes have not taken this lying down. Deprived of their luxurious bath of hydrochloric acid and assaulted with antibiotics, they have formed a global resistance movement, and in some places they shrug off the normal triple therapy of proton pump inhibitor, amoxicillin and clarithromycin. This large trial was set up in several Central American countries to see if a quadruple regime including metronidazole would result in better eradication than triple therapy given for two weeks, but it did not. Here the old stuff still works, and those wishing to prevent ulcers do not have to give up their beer and tequila for two weeks while enjoying their enchiladas.

BMJ  6 Aug 2011  Vol 343
A little study (called HONEST) from a Dutch renal clinic concludes “The findings support the combined endeavours of patients and health professionals to reduce sodium intake.” They took 52 outpatients with mild hypertension and proteinuria with an estimated glomerular filtration rate above 30 and gave them all a massive daily dose of lisinopril (40mg). They were then randomised to 6 week crossovers between a normal or low sodium diet (unblinded) plus placebo or valsartan 320mg. The low sodium diet reduced BP by 1mm Hg more than the valsartan. To be HONEST, I can’t see why this trial was even done, let alone published.

Screening seems to be the topic of the week in these journals and the hottest topic in screening is always mammography. Over here in the United States, it is an article of faith that annual mammography saves lives and that denying it to women under 50 smacks of death-panel socialism. In the UK, on the other hand, it is becoming impossible to find expert speakers willing to defend screening mammography in public: and that’s mammography every 3 years from 50-65. It’s becoming clear that for every life saved, 15 women undergo unnecessary surgery and hundreds undergo the anxiety of further investigation. And here is a study looking at the impact of screening in several European countries, comparing adjacent areas where it was introduced many years apart. “Our study adds further population data to the evidence of studies that have used various designs and found that mammography screening by itself has little detectable impact on mortality due to breast cancer.”

Ann Intern Med  2 Aug 2011  Vol 155
137    In the National Lung Screening Trial reported in the New England Journal, the rate of transthoracic needle lung biopsy following a positive CT or X-ray was only 2-3%. On the other hand, if such a screening programme were scaled up, this would still mean an awful lot of people. Here the authors of the book Overdiagnosed which I recommended above, plus their Dartmouth colleague Ronda Wiener, look at the risk of complications following such a procedure. They studied the outcomes of nearly 16 000 transthoracic biopsies, mainly performed for the confirmation of peripheral lung cancer. Haemorrhage is a rare complication, but can be life-threatening; whereas pneumothorax, at 15%, is far from rare. With more helical chest CTs being done for all sorts of reasons, and a quarter of them revealing pulmonary nodules, order in some extra chest drains.

171   I recently shocked an audience of young doctors by stating that my chance at 61 of having localised prostate cancer stood at about 25%. Since then I have looked at various sources (including Overdiagnosed) and found that according to one study of prostates examined histologically after traumatic death, the true figure may be 60%. So if a urologist decided to do some transrectal biopsies on me and hit the right/wrong spot, I might well have a cancer diagnosis. So what would then be the best nonsurgical management strategy – leave alone, local radiotherapy (brachytherapy), or external beam radiotherapy? The conclusion of this systematic review of different modes of radiotherapy for localised prostate cancer is that nobody actually knows. A most reassuring fact to share with your patients.

Plant of the Week: Campsis radicans

This gaudy native of southern North America made it across from Virginia to England very quickly – perhaps before 1650. South of New York it is an unstoppably vigorous climber which will clamber over and suffocate or pull down anything in its path. But it seldom gets that rampant in our cloudy isles, and worse still, it often doesn’t bother to flower at all, unless carefully grown against a sunny wall. This wall must necessarily be of stone rather than red brick, so as to set off its loud and cheerful trumpets of scarlet, yellow, or orange. Pale south Oxfordshire oolitic limestone is ideal, if only the campsis would flower more often. When it does, its flamboyance is a wonderful corrective to the tasteful, hydrangea-and-rose dominated August gardens of that genteel part of England.

This plant does not mind cold – it is apparently hardy to minus 30C, and grows well in southern Canada: it just needs plenty of summer sunshine. Its commonest name is the trumpet vine or trumpet creeper, though its other American name, “cow itch vine,” hints at earlier, earthier times in ol’ Virginny.

JAMA 27 July 2011 Vol 306
The management of early invasive breast cancer has evolved gradually though improved understanding of its natural history together with improved deployment of chemotherapy and radiotherapy. We also now have better ways of detecting micrometastases in lymph nodes and bone marrow and this American study reports on their prognostic significance at a median of 6.3 years. In the context of modern treatment, the presence of micrometastases in sentinel lymph nodes has no effect on disease-free survival. The presence of bone marrow micrometastases is uncommon, and perhaps a little more ominous: but the confidence intervals are so large that it would be unwise to read too much into this. Best to wait for even longer follow-up.

David Simel’s Rational Clinical Examination has been the best series in any of the medical journals I have reviewed over the past 13 years, but recent choices of topic have strained the limits of the format somewhat. This piece which asks “Does This Patient Have Medical Decision-Making Capacity?” is an invaluable addition to the series, but it also illustrates the problems of straying into territory where there the gold standard is simply “expert opinion”. This is exactly what evidence-based medicine is supposed to deliver us from, and given such a comparator I don’t think it means much to apply the concepts “sensitivity” and “specificity” and then subject these to statistical analysis. Predictive values are always population-dependent; here they also vary from day to day and from situation to situation. We are dealing with human cognition and choice, not subarachnoid haemorrhage or pyelonephritis. But never mind: we should all be grateful for the authors for doing the best possible job, and everyone who shares decision-making with elderly patients should have the open-access Toronto instrument ACE (Aid to Capacity Evaluation) immediately to hand, while relegating the MMSE to occasional other uses in patients with gross dementia.

NEJM 28 July 2011 Vol 365
“Hats off, gentlemen, a genius!” wrote Robert Schumann when reviewing a newly published piano piece by the then unknown Polish composer, Frédéric Chopin, in 1831. Every now and again – maybe once a year – you’ll read a medical paper which gives you the same feeling. The technical aspects of this study are very simple; the numbers are not huge; but the intervention works, and people who would otherwise die will henceforth remain alive. The intervention here is desensitization to HLA in patients awaiting renal transplantation who have become sensitized to HLA through previous transplantation, blood transfusion or pregnancy. The wait for a suitable donor for such patients can be endless, so that the survival advantage for the desensitization group who are able to receive immediate transplantation gets larger as time goes on. Just as Chopin’s Variations on Là ci darem la mano stood out amongst the trashy repetitive virtuoso pieces of the early 1830s, so this study stands out among the usual garbage of statistics-squeezing and clinical irrelevance that fills most of our medical journals. “Hut ab, ihr Herren, ein Genie!”

And now back to the familiar world of market-driven drug trials and their quaint little ways. The only interventions which reduce progression to end-stage renal disease in type 2 diabetes to a clinically significant degree are blood-pressure lowering drugs. In this phase 2 trial, funded by Ream Pharmaceuticals, bardoxolone methyl was given to type 2 diabetic patients with an estimated glomerular filtration rate between 20-45. In the first few weeks, patients given the drug at various doses showed an increase in eGFR of about 10 units which was sustained for the duration of the trial. Also, compared with placebo, they had twice the rate of GI side-effects and muscle cramps, and about 80% more incident hypertension. “The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD.” says the Conclusion. Lord help us.

Lancet 30 July 2011 Vol 378
One of the most depressing aspects of generalist medicine is being constant reminded of the penalties of old age, particularly dementia. I am not at all surprised at the result of this landmark British trial of two antidepressants, sertraline and mirtazapine versus placebo in patients with moderate dementia and symptoms of depression, 85% of them still living in the community. These drugs made no difference at all to those with depressive features such as lack of interest or enjoyment in food or company, or a wish to die. Such feelings, alas, may come with the territory for many old people who are aware of declining cognition.

Last week we read about the failure of a “vaccine” against GAD to halt the progression of type 1 diabetes. It seems to me that the problem lies in the fact that by the time children and adolescents present with the condition, the great majority of their beta-cells are already destroyed. Unless somebody finds a beta-cell specific regeneration factor, all you can hope to do is to keep the remaining horse in the stable while the rest have bolted. So I have grave doubts as to whether the use of specific immune suppressants, such as abatacept, will ever lead to useful treatments for type 1 DM. Abatacept inhibits the generation of autoaggressive T-cells and is already used in rheumatoid arthritis and psoriasis: here it is shown to inhibit the destruction of beta-cells as assessed by stimulated C-peptide production. But the effect wore off after 6 months: clinically, this does not seem like a promising approach, unless we can find ways to spot the disease process at a much earlier stage.

BMJ 30 July 2011 Vol 343
Here is the seventh meta-analysis to show that intensive glucose reduction in type 2 diabetes is generally pointless and can be harmful. Three years after ACCORD and ADVANCE, I think it is time we now moved into a post-Copernican view of T2DM: the sun does not revolve around blood sugar levels, and the popes of diabetology who have declared otherwise should withdraw their bull. Or should that be bulls? Something like that, anyway. We now know some useful things about older white people with T2DM but our ignorance about the rest is immense. Is there anyone out there who might want to set a new research agenda around Patient-Centred Care for Type 2 Diabetes? Beginning with an open-access text summing up current knowledge from the perspective of individual patients – say a Bangladeshi woman of 39 with five children, or a Chinese man of 58 who has just had an MI, or an otherwise healthy Italian of 73: does one size fit all? If a project like this interests you, I’d love to hear from you at richard.lehman@yale.edu.

Diverticular disease has been labelled a “disease of Western civilization” and it remains fashionable to attribute it to a lack of dietary fibre. The nearest thing to dietary fibre I ever saw as a child was the statutory radish which accompanied formal afternoon teas with limp lettuce, slices of tinned meat and processed cheese accompanied by white sliced bread: all vegetables were cooked to a pulp and fruit was mostly tinned peaches on special occasions. Since the introduction of edible food to the British Isles, rates of admission for diverticulitis have soared. I do not believe the fibre hypothesis, but see if you do after reading this paper from the EPIC-Oxford study. As usual in dietary studies, the authors discuss all the limitations of their data but then go on to declare that “these findings lend support to public health recommendations that encourage the consumption of foods high in fibre such as wholemeal breads, wholegrain (unrefined) cereals, fruits, and vegetables.” OK: eat grainy bread if you like it. Or avoid sitting while defecating, if you prefer that particular theory of diverticular disease causation.

Do you remember SnNout? This is the rule that a test with a high Sensitivity rules a condition out if it is Negative. It belongs to one of the earlier chapters of Dave Sackett et al’s Clinical Epidemiology in its classic second edition. Very high sensitivity is an essential quality for all tests that are used for the detection of immediately life-threatening conditions. This excellent Canadian prospective cohort study finds that this is the case for modern computed tomography performed within six hours of headache for suspected subarachnoid haemorrhage. So if you work in any setting where such patients first present, you must have a high index of suspicion, and insist on an immediate CT. If you dither, or take no for an answer, you will miss one: the track record of British GPs in this respect is nothing to be proud of.

Arch Intern Med 25 July 2011 Vol 171
Rumour has it that our dear government would like to introduce 28-day readmission rates as a quality marker for hospitals. Here over the pond they prefer to count to 30 days, and how the data will be used is anybody’s guess: the longer I spend in a unit which scrutinizes the American health system, the more I feel that it can’t be long before the Mad Hatter appears with a chorus of singing oysters. This study investigated the real-life efficacy of a the Care Transitions Intervention, which is a package of better physician communication and patient education, shown to reduce 30-day readmission by 30% in the setting of a randomized controlled trial. Applied to Medicare patients in 6 Rhode Island hospitals, it had about half that effect size. The title of the accompanying editorial says it all: Interventions to Decrease Hospital Readmission Rates: Who Saves? Who Pays? Good questions to ponder in any market-based health system. Thank goodness we don’t have any of that nonsense in the NHS.

Here is another illustration of the same phenomenon with patients readmitted to hospital with heart failure. The intervention was “an advanced practice nurse–led transitional care program for patients with heart failure”. We have been here before, starting with Lynda Blue in Glasgow circa 1998. Like all supportive interventions for heart failure, this started with modest success in small trials and became less successful with time. And why? Because heart failure patients inevitably get worse from time to time, and call for an ambulance when they are feeling about to drown, knowing that outside office hours that is surest way to get help. In hospital they get intravenous diuretics and oxygen, they are monitored and nursed, and discharged as soon as possible on much the same treatment as they were on before. Unless we develop miraculous new interventions for failing hearts or
better models of 24-hour care in the community, this pattern will continue.

Plant of the Week by Eric Larson of Marsh Botanical Gardens

PLANT OF THE WEEK
June 23, 2010
Dublin Bay Rose
Rosa x ‘Dublin Bay’

I have had more questions about this plant than a zookeeper during elephant mating season. It is sited perfectly to provide an entrance “wow” as you come off the street on Mansfield, admittedly not our best first impression. If you can look past the dump area that grounds maintenance uses for organic waste, a thirty yard dumpster, a five yard dumpster, another container for storage of tools, the sand and salt mixing area with metal and canvas canopy, you will raise your eyes to the completely charming and very assuming Dublin Bay Rose.

This wonderful rose has been blooming for six weeks now, which is very unusual for a climbing rose. I don’t spray it, I don’t prune it, I don’t pamper it, I hardly even tie it to the fence (although I will this week, I promise). It rewards my benign neglect with nothing short of extraordinary blooms of the deepest red.

Did I say that is also fragrant? When you cut a bouquet of these roses, you won’t be sneaking up on anybody. They extend their presence into the room like a queen sending her entourage ahead of her. The darkly scented aroma is a favorite in our household, because it takes a queen to know one. That queen being my lovely wife, of course.

Dublin Bay Rose, like all roses, prefers full sun, well-drained soil and good fertility. Like most climbing roses, it will grow pretty rampantly up and to the side. Unlike many roses of any kind, Dublin Bay seems to enjoy a life unfettered by the debilitating effects of fungal and bacterial problems. As I mentioned earlier, if there is a truly carefree rose, it is Dublin Bay.

The rose is a member of the eponymous Rose family, Rosaceae, which includes a wide array of plants from apples, cherries and similar fruits to Raspberries and other brambles, from Hawthorns to the lovely little Potentilla. There are about a hundred genera within its ranks, and almost three thousand species. Most species in the genus Rosa are native to Asia, with a few from Europe, even smaller number from North America and a very few from northwest Africa. There are numerous cultivars and hybrids of rose adding to the genetic pool, creating a botanical nomenclaturists nightmare or job security, depending on your viewpoint.

For instance, if you google Dublin Bay Rose, you’ll get alternate names, including “Improved Blaze” and “Don Juan.” I prefer Dublin Bay for some reason, don’t ask me why. The naming of plants, especially specific cultivars, is complicated. If you “discover” a “sport” or a variant genotype of a plant, you can name it. But that same sport may have already been discovered and named by someone else, setting up a potential Jerry Springer-type conflict. Speaking of naming rights, James Thurber wrote a wonderful piece about a woman whose husband studied insects. She complained that his colleague, a botanist, named wonderful flowering plants after HIS wife, while her name gets immortalized on some creepy crawly thing. Ah the foibles of our species.

Come see the Dublin Bay rose soon, or plan to visit in September, when its lovely blooms will reappear in that special time for all roses, June and September (and for some on into October). The flush of bloom at those times seems to be a phenological indicator of Homo sapiens’ need to ritualize our relationships. Nice to have roses for the wedding.

Eric

“Plant of the Week” and “Liquid Sunshine” are sent out almost-weekly, sometimes weakly. They do not reflect the corporate or organizational views of Yale University, Marsh Botanical Gardens or any other rational entity. For complaints, contributions and more information, please contact: Eric Larson at 203-432-6320 or eric.larson@yale.edu

RL’s Note for British Readers: Eric is right: this is a really great rose. It is so intensely red that photographs of it look unreal. It is reliably repeat flowering – continuous from June to October or even November in our English garden. Eric is also absolutely right about its freedom from disease, and its general imperturbability: we grow it on limy clay in cool cloudy Oxfordshire, he grows it on acid sand in baking New England, and it flourishes on both. But I think it must need the New England climate to produce scent; back in Old England we can only just pick up a hint of apples on warm evenings.

JAMA  20 July 2011  Vol 306
277   As I try to write, much of America lies torpid in a heat wave approaching 40 degrees centigrade. This issue of JAMA, like last week’s, seems to suffer from a sort of anticipatory heat stroke – not one of the research papers  belongs in a generalist journal, and some of the commentary pieces really don’t belong anywhere. Perhaps it’s just me being irritable from the heat, as I sit lightly clad under a ceiling fan, sipping iced water. Takotsubo cardiomyopathy is a clinical curiosity which you are never likely to encounter unless you are a cardiologist in a tertiary centre, so the real achievement of this study was to collect 256 cases from Europe and North America. This is a form of acute heart failure in the absence of established heart disease, characterised by apical ballooning in most cases and complete recovery in all. The great majority of sufferers are postmenopausal women who have been subjected to some form of major stress, either physical or emotional. They managed to get all these patients into a magnet while they were still symptomatic and took some very nice pictures of ventricles looking like squeezed balloons and then going back to normal.

302   Here’s a commentary piece with the intriguing title, Prevention of Melanoma With Regular Sunscreen Use. Is melanoma caused by sun exposure? I don’t think anyone really knows. Previous papers have suggested that regular sunscreen use might even cause melanoma; whereas the two American authors here cite an Australian study as convincing evidence that using sunscreen will prevent melanoma. This was a ten-year follow up study of a four year intervention (lots of free sunscreen, applied to the head, neck and extremities) which demonstrated a “reduction of the observed rate of melanoma in those randomly assigned to daily
sunscreen use (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.24-1.02; P=.051).” In other words, the result did not reach significance. In fact the Journal of Oncology subsequently published a letter convincingly criticizing the methodology of this study and noting that the results could equally be interpreted as showing that sunscreen increases melanoma on the treated areas. But our earnest commentators nonetheless go on to advise the liberal use of sunscreen on large areas of the body which were specifically excluded in this study, and conclude their piece with the categorical claim that “Regular use of sunscreen can effectively reduce the risk of developing melanoma for at-risk individuals”. Enough: if you are interested, you can make up your own mind, as the Journal of Oncology has an open access policy. You can even write a letter to JAMA if you so wish. I am too hot and bored.

NEJM  21 July 2011  Vol 365
213   Collectors of choice studies from Framingham must add this classic to their collection. You couldn’t wish for a better teaching paper for advanced students of surrogate outcome measures and predictive scoring systems plus the statistical data interrogation methods you need for each. But there are some lessons for the ordinary clinician here too. Carotid intima-media thickness is often touted as an important tool in cardiovascular risk assessment that’s easily measured by ultrasound. Here nearly 3,000 members of the Framingham Offspring cohort underwent measurement of their carotid arteries and were followed up for just over 7 years, during which there were 296 events. The upshot is that maximal CI-MT adds little to conventional Framingham scoring except at the extreme upper values. It matters a lot how carefully you do the measurement as well. Far from being a cheap, quick way of improving CV risk measurement, CIMT remains a research tool; and even then, like all surrogates, is only useful for hypothesis generating, not for clinical decision-making.

231   Has it ever struck you that although eczema and psoriasis are very common, you hardly ever see them both together in the same person? Or indeed that eczema frequently gets infected while psoriasis does not? Perhaps these observations are so commonplace that no dermatologist ever bothers to mention them, while I was too dim to notice till quite late in my career. Anyway, the answer may well lie in T-cell function. Atopic eczema arises from a systemic Th2-cell–dominated immune shift characterized by frequent elevations of total and allergen-specific IgE levels. In psoriasis, by contrast, Th1 and Th17 T-lymphocytes drive a process which is mediated by interferons and interleukins. That’s the easy bit. If you want to know how these lymphocytes fight it out in those rare patients who have both conditions at the same time, go to this paper which examines three cases from Germany and Italy in minute immunochemical and histological detail.

239   Here is a good Italian-British-Australian update on Febrile Urinary Tract Infections in Children: “the most common serious bacterial infection in childhood,” as the opening sentence announces. So everybody who deals with febrile kids should read this piece: but I know that not many of you will. If you’re a jobbing clinician in the developed world, that would mean either subscribing to the NEJM or ordering a copy of the article from your local medical library: if you work in a part of the world where these infections create the highest morbidity, your chances of being able to afford this are close to zero. Sadly this applies to clinical reviews in all the journals I regularly review here, even the BMJ, which made a retrogressive commercial decision some years ago. If you want to do something about it, join HIFA2015, and write or edit your own review for Wikipedia, the most accessible and most accessed source of medical information in the world. And if you don’t think a Wikipedia article is very good, that’s your fault: get in there and make it better.

266   Now here is how it should be done: a case-based discussion of the Treatment of a 6-Year-Old Girl with Vesicoureteral Reflux – educative, interactive, web-based, and free. Three treatment options are presented: watchful waiting, prophylactic antibiotics, and reflux surgery. Persuasive cases are made for each and then debated on-line. Yet the review article (above) which would inform debate is for subscribers only.

Lancet  23 July 2011  Vol 378
319    It was a neat idea; it worked in a mouse model of type 1 diabetes; unfortunately it didn’t work in people. Good double-blind randomized trials with clear results are always a triumph for clinical science, however disappointing they may be for investigators and patients. The auto-immune process which causes catastrophic beta-cell loss in type 1 DM is heavily targeted towards glutamic acid decarboxylase (GAD), and animal experiments suggested that introducing exogenous GAD with adjuvant (alum) would modify this response. So 145 human subjects with recent onset T1DM were randomized to receive “immunization” with GAD alone, GAD with alum, or alum alone. Nothing happened: so we can move on, either to different experiments with the GAD pathway or with other approaches.

328   Early stage prostate cancer can be cured with radical prostatectomy, performed as an open retropubic procedure. Early stage prostate cancer can also be treated by external beam radiotherapy. Early stage prostate cancer can also be left undetected and untreated, and only a small proportion of it will ever progress to end-stage disease. All of which makes it very difficult to discuss with a patient who has just been given this “cancer” diagnosis. Should he wait and take his chances? Or should he go for surgery, knowing from this British study that 75% of men will be incontinent after radical prostatectomy and that pelvic floor exercises will not improve the situation, even if they are carefully supervised? If it’s a choice between a 15% chance of dying from the cancer and a 75% chance of being incontinent for the rest of your life, which do you prefer? Ah, how sweet are the joys of being an elderly male.

This paper also reports a parallel study of men rendered incontinent by transurethral prostatectomy for benign disease. They too did not benefit from supervised pelvic floor exercises.

348   If you went into medicine to do the most good to the greatest number of people, then why aren’t you in vaccine research? The Lancet is running a short series on vaccine development, singling out Edward Jenner and Richard Moxon for special praise, and inviting the latter to co-author an overview of what the next decade might hold. Vaccines for HIV and malaria? Multivalent vaccines for every type of meningococcus and pneumococcus and influenza virus? Just imagine if you could claim credit for one of those. You really would deserve a bronze statue and a blue plaque on your house.

BMJ   23 July 2011  Vol 343
Nursing homes full of dementia patients are the inevitable price we pay for the advances in medicine which permit longevity, and they are places where doctors should be encouraged to spend more time (I mean prior to retirement, not after). I am sorry to reflect on how un-proactive I often was in the care of these patients – salving my conscience with the thought that in the institutions I served, the nursing staff were generally reliable and – importantly – kind. This cluster-randomized Norwegian trial looked at the effect of a graded analgesic protocol on agitated patients who could not report pain. This was at least as successful as treatment with psychoactive drugs, and probably both safer and kinder. There can never be certainty in studies of this sort, but this at least reminds us that it in an agitated demented patient, one should always look for a source of pain – and also for infection.

Had I been responsible for this Canadian retrospective cohort study of pre-operative echocardiography, I think I would have submitted it to the Archives series called “Less is More.” Maybe they did, and got the BMJ as second prize. No matter: the message is that medical fashions often run riot before anyone stops to say, “Do we really know why we are doing this?” Apparently pre-op echo for major non-cardiac procedures has become a standard procedure, almost a hallmark of quality, in many North American hospitals. For all I know, it may be catching on in the UK too. From the evidence of this study, it has zero effect on patient outcomes. Probably the quickest way to stop it being done would be for North American insurers to stop paying for it.

Ann Intern Med  19 July 2011  Vol 155
87    Steven Woloshin and Lisa Schwarz have been researching better ways of discussing the benefits and harms of treatment with patients for many years: their little book, Know Your Chances (2008) is a must for every practice library. Here they present a randomized trial which overturns the widely stated dogma that people understand risk best when it is expressed as natural frequencies i.e. number per 1,000. In the trial, randomly selected US adults were tested on their comprehension of figures given per 1,000, vs. whatever gave a numerator above 1, vs a percentage. Plus two combinations. It seems that people understand percentage data best, but a third failed the test outright. So here is another “rule of thirds” in medicine: a third of patients understand what you tell them perfectly; a third understand it a bit; and a third don’t understand however hard you try. The last group are nowadays said to have “poor health literacy” and if you like this classification you can find out how it affects health outcomes in a systematic review on p.97. No prizes for guessing.

108   Out-of-hours primary care is an important domain of clinical practice which largely lacks its own literature. Just yesterday I addressed a mixed audience of doctors and researchers from the USA, Brazil, Iran, India and China on the subject of “How Do Our Health Systems Really Work?” and it was interesting to note that out-of-hours care is provided in a similar way in most health systems – by a mixture of primary care centres and hospital emergency departments, with a lot of overlap in case-mix. Judging from this narrative review of OOH primary care in the Netherlands, they are the world leaders in quality and speed of response – an average of 30 min for a non-urgent home visit, for example! Of course it helps that you can practically cross the whole country on a bicycle in that time. But the thing they haven’t quite solved is how to integrate the working of their primary care centres with their hospital emergency departments. Time for a collaborative British-Dutch study I think.

Plant of the Week: Aesculus parviflora

As July turns towards August, there are so few interesting large plants in flower that longstanding readers must forgive me a bit of repetition. I’ve praised this shrubby horse chestnut in previous years, and even commanded you to plant it if you have a large open garden that I might visit in August. It needs lots of space, because it is broader than it is high and suckers freely. There is a lovely specimen in the Botanical Gardens of Sheffield, covered in tall white candles of flower for a fortnight during the summer holidays.

Now there are a few good examples of this plant here in New Haven, and I was looking forward to seeing them in flower. One is on my bus route to work and was quite resplendent for a day. The next day the flower spikes were brown, and now they are just curly remnants, thinking of producing conkers of their kind. The summer heat must be to blame, you would think: but in fact the “Bottlebrush Buckeye” comes from much further south in the USA, in Carolina, Georgia and Florida. From there it was brought to Britain by John Fraser in 1785, from which time it was distributed so successfully that by 1820 it was “to be met with in most of our nurseries.” 

I think that this is a rare instance of a plant that might look better outside its natural habitat. In the USA, it just behaves like an impatient organ of reproduction: wham, bang, here are my conkers. But on the cloudy Pennine slopes of Sheffield, 20 degrees north of its natural latitude, it takes it slow and provides joy for weeks.

JAMA  13 July 2011  Vol 306
Unusually, I couldn’t find anything to report on from JAMA this week. Last week, its new editor, Howard Bauchner, promised us a new vision for the journal. I liked the old journal very much but it was becoming like an old jumper *– full of comfortable associations but saggy with holes and patches. I hope HB realises that the days of “high prestige” printed journals are coming to an end, and that by the end of his editorship we need to have an open-access, interactive JAMA.

*For American readers I should explain that a jumper is a kind of British knitwear which approximately covers the thorax. It is usually exchanged at Christmas, and in extreme cases is hand-knitted.

NEJM  14 July 2011  Vol 365
107   When you read the word prostate in the title of a paper, expect confusion. And be accordingly grateful if you come away slightly more enlightened than before you read it, as in the case of this study of Radiotherapy and Short-Term Androgen Deprivation for Localized Prostate Cancer. As a result of a carefully designed trial which began in 1994, we can be reasonably certain that for localized prostate cancer of intermediate Gleason score, it is worth giving a few months of androgen suppressing treatment around the time of external beam radiotherapy. In fact this can only be deduced from a post-hoc subgroup analysis, and the effect size is not large. But there is a balance to be discussed with patients here, with a single-figure percentage increase in long-term survival to be set against a short-term increase in impotence and myocardial infarction.

119    Here is a study which should make all doctors squirm a bit. We are all committed to honesty, I hope, both to ourselves and our patients. And yet repeated studies of the placebo effect show that our honesty can deprive patients of large subjective benefits. For example, we all know of patients with real or presumed asthma who consume enormous quantities of beta-adrenergic inhalers without any objective evidence of severe bronchoconstriction. A few of them probably die as a result. We suspect that they would get equal symptomatic benefit using a harmless placebo inhaler, and this pilot study from Harvard goes some way to demonstrating that. I say “some way” because the study seems to have timed the interventions to suit the investigators, not the patients. They received inhaled albuterol, inhaled placebo, sham acupuncture or simple waiting in cross-over fashion for a total of 12 visits. Inhaled albuterol was the only intervention that improved FEV1 but sham acupuncture and placebo inhaler were as good at relieving symptoms. For thousands of years, doctors were safer using placebos than active treatments; and that probably applies in certain areas today. But to use placebos deliberately is to become a charlatan and to undermine the scientific basis of medical progress. Discuss.

P.S. One of the authors of this study declares direct payments from 20 pharma companies and grants from 9: it would be nice to think he will be doing similar studies on all their products.

Lancet  16 July 2011  Vol 378
This week’s Lancet is devoted to HIV/AIDS, and as some readers will know I have traditionally refrained from commenting on this topic because its global importance is in no way matched by my personal experience of fewer than 10 patients, managed entirely by others with proper expertise. Rilpivirine is the latest anti-retroviral drug to be added to their armoury, and I will leave them to use it according to the evidence provided by two randomized controlled trials.

However, it has been one of the most telling experiences of my professional life to have witnessed the whole HIV/AIDS story unfold,  from the mysterious, uniformly fatal “gay plague” of the early 1980s to its present status of a controllable chronic disease affecting large parts of the resource poor world. It has shown us what can be done when the will is there – even George W Bush and some pharma companies come out with some honour in this story – and also what cannot so far be done. For example, I do not give much for the chances of those who want to change the behaviour of men who like to have concurrent sexual partners. And the usual answer to a viral pandemic – an effective vaccine – has been desperately slow in coming, though hope is returning. For this and much else, it is worth reading the review of HIV prevention on p.269.

BMJ  16 July 2011  Vol 343
Ever since the first trials showed that statins reduce cardiovascular risk by about 20%, there have been two schools of thought, the “put ‘em in the water supply” school and the “use our risk score” school. Remember that statins are the only lipid-lowering drugs that have been shown to reduce CV risk, and that they do so without a threshold effect, measured by total or LDL cholesterol or anything else. Whatever your cardiovascular risk, a statin will lower it. Age is a key factor of course: so most guidelines which are based on absolute risk advise more and more statin prescribing as people get older. Not so the subtle Norwegians: they base their advice on the value of the years gained, and this is how the BMJ has printed their suggestions:

• 0-49 years: if 10 year risk of cardiovascular death is ≥ 1%
• 0-59 years: if 10 year risk of cardiovascular death is ≥ 5%
• 0-69 years: if 10 year risk of cardiovascular death is ≥ 10%

Spot the misprints.

If you are a full-time British GP, you are likely to see a child or young adult present with type1diabetes once every decade. I was such a GP for 31 years and saw two, both within the space of two weeks. Such is the play of chance, and it so happened that neither presented in full diabetic ketoacidosis. Does that make me a good GP, or just a lucky one? Certainly we don’t want kids presenting in DKA, so this systematic review looking at the reasons they might is useful: but lack of primary care awareness is only one of many potential factors.

What are the circumstances that favour the introduction of a useless intervention? I would say they are: perceived unmet need; a plausible mode of action; strong willingness for both patients and doctors to try out a new treatment; and financial gain for those supplying the treatment. Actually it doesn’t even need to be a treatment: it could equally well be a diagnostic test e.g. for cancer. We’ve seen it for one weight-reducing drug after another; we’ve seen it for one medical device after another: here we see it for vertebroplasty for recent vertebral fracture. Individual patient data from two randomised trials were pooled and showed no subgroup in which the procedure gave better results than placebo.

Arch Intern Med  11 July 2011  Vol 171
1150   Throughout my GP career I held on to two beliefs: if patients wanted to be seen the same day, it was our business to see them: and that general practice was the art of doing medicine in ten-minute consultations, so it was unprofessional to run late. Putting up barriers and messing about with appointment systems implied that we were somehow not there to serve patients, despite the increasing sums that they (as taxpayers) were providing for our comfort. This excellent systematic review of advanced access scheduling outcomes gives a thoughtful overview of the evidence from the UK as well as the USA on the effects of initiatives to achieve same day access. Unfortunately the studies are of too poor quality and too limited generalizability to reach any firm conclusions. Just do what is right by patients.

1183   The effect of sodium and potassium intake on mortality is a matter of deep communal belief which it is unwise to challenge. A recent European study which showed an inverse relation between measured sodium excretion (as an objective measure of sodium intake) and cardiovascular mortality was the subject of an immediate attempted rebuttal in The Lancet on the basis of insufficient sampling. Whereas this prospective cohort study of 12 000 US adults, based on the remarkably accurate methodology of recollected food intake, will bring comfort to the traditionalists. Sodium – he bad. Potassium – he good. Just wait for my Good Death Cookbook.

Plant of the Week: Lagerstroemia indica

By sheer fluke, the place we found to live in the USA over the summer is directly opposite the Marsh Botanical Gardens at Yale. Now Yale is a rich university, occupying the centre of New Haven and gradually eating up the town, particularly the desirable parts of the northern end. Here the original gardens were laid out by Beatrix Farrand, the most famous American garden designer of her time, a Gertrude Jekyll figure who also designed the lovely grounds of Dumbarton Oaks in Washington DC. In the 1920s, Farrand wanted the gardens to be part of a scheme to make the whole Yale campus into a continuous collection of interesting and decorative plants.

Alas, when the US joined the war in 1941, the garden staff of the Yale Botanical Gardens were laid off, and they have never been reinstated. A large concrete building was plonked in the middle of the resulting wilderness in the late 1950s.

I was writing this column three weeks ago when I found the need to look up the fruit called Apriplum, and to my amazement I was directed to a column called “Plant of the Week” by Eric Larson of Yale Botanical Gardens. It turned out that we two people were writing a column with the same name, about 50 metres from each other.

Eric by himself is charged with the task of reviving the whole outdoor garden which in former days had a summer staff of 8. I wish I had time to help him. He has very kindly let me give you a sample of his delightful work – chosen at random, but to match the season. I have edited it slightly to remove references to social events and some of his musical activities:

PLANT OF THE WEEK
July 17, 2007
Crepe-Myrtle
Lagerstroemia indicaA plant that I saw in Kentucky reminded me of the plantings that I have done here at the gardens to hide a chain link fence. I planted the first stage of the shrub border in the summer of 2004, and it has started to perform its original function quite well, with the secondary function of providing ornament filing along behind.

The backbone of any shrub border, the skeleton if you will, is the evergreen planting. In deepest winter, it’s nice to have something green to remind us that all is not lost. Amongst the evergreens, I planted combinations that I thought might add to the mélange, while other combinations were completely a surprise to me. I always try to grow a few plants in the garden that I have never grown before, as an exercise in futility, utility or just plain fun.

A plant that I had grown before but in somewhat warmer climes is our Plant of the Week, Crepe-Myrtle. This large shrub/small tree is an excellent three-season plant, with something to recommend it to your attention during summer, fall and winter. Right now, it’s flowering here at the Gardens adding a top note to the madrigal in the shrub border.

Crepe-Myrtle flowers range from white to pink through the purple hues to red. They begin flowering in July here in New Haven, and will continue until frost, if you prune the spent flowers off. The blooms appear on terminal wood, or at the end of the branches of the current year’s growth. There is a range of flower-times depending on the variety, with “Hopi,” “Sioux,” “Yuma” and “Pecos” coming in early, followed by legions of other varieties, many named after tribes or individuals of the First People.

Back when I lived in Kentucky, I took a stab at a cut flower business, (New Giverney Gardens: Not Just In It For the Monet), selling flowers from buckets in a downtown Frankfort courtyard on Fridays using a bicycle-wheeled garden cart. Although I lost money, I learned a thing or two. One thing I found is that by playing guitar, I lured business in with a gusto that would make Barnum blush. But when I started to sing…well, let’s just say that business did not hum like a Singer. Another fact more pertinent to our topic today: Crepe-Myrtle makes a good cut flower for about a day, and then it drops its petals. But it is impressive as the centerpiece in the vase.

The leaves are arranged oppositely on the stem, emerge yellowish-green, bronze or reddish purple (well, that makes it a four season plant) in spring, changing to a nice medium green during the summer and then changing colors in fall. The fall color can be brilliant. Dirr has noted and I concur that generally the white-flowered varieties have a yellow fall color, and the pink/purple/red varieties can have orange, red or purple fall color. So plant a variety of varieties to enjoy maximum fall color.

After the leaves fall, the subtle winter effect can be more easily discerned as the “exfoliating” bark becomes evident. The bark is a gray color, but peels away in blotches much like the Sycamore tree, to reveal cinnamon brown, tan, darker gray or sometimes white. This effect is profound when backed up by evergreens or perhaps a brick wall. Some varieties have more contrast between colors in the bark, but they all provide some interest. This effect takes some years to develop, so patience is required.

Crepe-Myrtles are fairly easily grown, preferring full sun, average soil and little pruning. Prune to shape in summer, but not after August 1st: later pruning results in more winterkill. While this plant is hardy in zones 5-7, it sometimes dies in a late freeze within those climatic zones. By choosing a site wisely, one can forestall the problem.

While there are a few critters and microbes that beset Crepe-Myrtles, I have not had any problems here. Further south, aphids are known to chew on them, and there are acouple of fungal problems that crop up.

Crepe-Myrtles are members of the Lythrum family, Lythraceae. There are about 500 genera within this family, including the Lythrums, Pomegranate and our plant. The Latin genus name of our plant is after Magnus von Lagerstrom, a Swedish merchant and friend of Carolus Linnaeus. Myrtle may have been this man’s wife’s name. (Just kidding: Myrtle is from the two species of plants growing in the Mediterranean region. I’m not sure if the Crepe-Myrtle appellation refers to the French pancake-like treat or the cloth woven from silk. This plant is not related to the Myrtle genus.)

Plant of the Week is a publication of the Marsh Botanical Gardens. Opinions expressed herein do not reflect on the official policies of Yale University. Contact: Eric Larson (eric.larson@yale.edu)

RL’s Warning Note for British Readers: although crepe myrtles are hardy in New Haven to something like minus 25C, I have never seen a good one in England. They may not like our changeable damp, and I think they need hotter summers than we can offer.

JAMA  6 July 2011  Vol 305
45    Of all the great writers, only Chekhov captures exactly the balance of good and evil in rural life. Before his fame as a writer, he worked in a rural hospital, making the best of what support staff he had and what competencies he had acquired as a medical student in Moscow. To be a long way from specialist help was a precarious position for a doctor or a patient then, and is equally so now. Modern hospitals must have a certain critical mass to survive and be able to provide the basic range of core acute services: and which ambitious health professionals are going to choose to provide them, for the rest of their lives, on the tightest rota possible, in remote rural North Dakota? Not that Chekhov ever practised in North Dakota; but we are talking here about a study of American rural hospitals and their outcomes for myocardial infarction, heart failure, and pneumonia. Mortality is higher than for non-rural hospitals with much larger average acute bed numbers. Whether this will ever change is open to doubt: if you live in a huge country and want to enjoy the trees and sunsets described by Thoreau or Turgenev, you must not be surprised if the spectres of Chekhov and Bulgakov attend your sickbed.

53    By contrast, the down side of going to a big city hospital in America is that they will do too many things to you that don’t need doing. If you come through the doors of the hospital nearest to me in the middle of the night, you will get more investigations done before daybreak than you would get in a week lying on the average British medical ward. You will be at particular risk if an interventional cardiologist passes by and decides you need coronary angiography, because such persons tend to have a well-developed oculo-stenotic reflex – meaning that the moment they see a narrowed coronary artery, in goes a stent. By the time your bad heartburn has worn off, you will have had two of these placed in your nearly normal coronary arteries and had a dobutamine stress echocardiogram, a PET scan and an OGD. You will be home by lunch, consisting of aspirin, clopidogrel, labetalol, atorvastatin, lisinopril, and omeprazole. Quite filling. That’s my impression anyway: but the reality, as judged by this excellent study, is slightly less extreme. “In this large contemporary US cohort, nearly all acute PCIs were classified as appropriate. For nonacute indications, however, 12% were classified as inappropriate, with substantial variation across hospitals.”

NEJM  7 July 2011  Vol 365
32    About 30 years ago, it was discovered that the cardiac atria react to increased filling pressure by producing a hormone which promotes the excretion of salt and water, which was therefore called atrial natriuretic peptide (ANP). Then about 20 years ago another natriuretic peptide was isolated from pig brain and called brain natriuretic peptide (BNP). This was unfortunate, since BNP is not a significant brain hormone but a very significant cardiac hormone, almost entirely produced by the ventricles of the heart (not the brain). So nowadays we sometimes call it B-type natriuretic peptide, to avoid confusion with pig brains and British nationalist parties. Since then, various people (myself included) have been looking at ways of using circulating levels of BNP to help clinical decision-making, with mixed success. But it also occurred to pharma companies early on that by using some of the basic peptide structures common to ANP and BNP, they might be able to produce a new agent for use in acute heart failure. Nesiritide was granted a licence by the US Food & Drug Administration for use to relieve dyspnoea in AHF after a small, company-funded trial compared it with intravenous nitrates. I was amazed at the FDA decision then and I’m not in the least surprised that this large, publicly funded, placebo-controlled trial shows that it has no place in the management of acute heart failure.

62   A nice straightforward clinical review takes us through the management of glucocorticoid induced bone disease. Loss of bone occurs because steroids increase the lifespan of osteoclasts while dramatically suppressing the numbers of osteoblasts. So it’s no surprise that osteoclast-suppressing drugs are more effective than others like PTH or strontium at preventing steroid osteoporosis. If I were in the position of having to take long-term prednisolone, I think I’d opt for once yearly IV zoledronic acid rather than weekly alendronate, especially since treatment needs to continue as long as the steroids are needed.

Lancet  9 July 2011  Vol 378
129   In this diabetes-themed issue of The Lancet, here is a nice piece of pragmatic British research – and pragmatic in this case is not just a polite term for methodologically sloppy. The trial looked at what happened if you took two groups of newly diagnosed type 2 diabetics and randomised them to usual care, usual care plus an intensive diet intervention, or usual care plus the diet and extra exercise. The diet did something to lower weight, glycated Hb and blood pressure – not a lot, but possibly enough to be useful – whereas the added exercise produced no further benefit in these short term proxy measures. So it may be worth concentrating most effort on diet in this group – but I am by no means convinced that we know what the ideal diet actually is, or that exercise might not be equally or more beneficial in the long term.

147    If I go for a pre-operative check, that means I intend to have an operation; if I have a pre-prandial blood test, that means I intend to have a meal; but if somebody tells me I have pre-diabetes, that means I shall probably never get diabetes. Welcome to the whacky world of disease mongering, where you are a living disaster area just waiting to happen. It’s a wonder that any of us get out of this place alive, as Sir Richard Doll once said. “Pre-diabetes” and “pre-hypertension” means that you don’t have a defined risk factor now but you have an increased risk of it in the future, just because of your place on a normal distribution curve. So, according to this Japanese study looking at the predictive value of various levels of HbA1c and fasting blood sugar, you should be “targeted.” For what? Some new intervention with a NNT of 500, perhaps: I can feel them inventing it now. For heaven’s sake, there are already 400 million people in the world with real diabetes who have difficulty accessing the treatments they need.

156   Our evidence base for the treatment of type 2 diabetes is not exactly one of the glories of medical science, but at least we can be fairly sure from the UKPDS and STENO studies that early intensive treatment of both glycaemia and cardiovascular risk will improve long-term outcomes. The ADDITION-Europe trial was led from British primary care by Simon Griffin and powered to show a decrease in real adverse hard end-points based on event rates in past T2D trials. The aim was to demonstrate the benefits of early target-driven intensive management in patients with T2DM detected by screening, but it failed to reach significance. “Usual care” for type 2 diabetes in Europe is now so good – as evidenced by much lower event rates than expected – that “intensive” care doesn’t add anything.

169   Learning time at The Lancet tends to be a heavy affair, as learned authors parade their knowledge and attempt to distil the content of a vast array of references (140 in this case). This three-author piece on type 2 diabetes across generations is certainly weighty but also fascinating, as it explores the various theories of T2DM pathogenesis. Early life nutrition seems to be their favourite hypothesis, in which case there’s not a lot we can do to stop the rise of the diabetes pandemic in present adult generations. This well-illustrated overview is well worth accessing and keeping to read properly on some rainy day: unfortunately the weather is hot and sunny in New England today and I need to take some exercise to get rid of abdominal fat and lower my fasting blood sugar.

182   The next magisterial overview concerns the Management of type 2 diabetes: new and future developments in treatment. Gosh this is exciting; and complicated; and depressing. So much astonishing ingenuity and painstaking discovery; so many promising leads; so little hard evidence. If you are to give drugs to 400 million people, perhaps for the rest of their lives, you have to be very very certain that you are doing more good than harm. The good you do must consist of a reduction in cardiovascular disease, in blindness, in amputations, and in kidney failure. If the blood sugar goes down too, that’s nice, and easy to measure. But the real end-points that we must know in order to practise safely take many years to measure, and until we know them we may be doing patients more harm than good – a situation positively encouraged by the present drug licensing systems both in Europe and the USA. Just look at the table of new drugs on pp.184-5 and see how often “Unknown long-term safety” features prominently in the right hand column. The sad fact is that therapeutic progress in type 2 diabetes must take longer and be better scrutinized if it is ever going to be safer, or more effective – see the piece on rosiglitazone (Avandia) on p.113.

BMJ  9 July 2011  Vol 343
“Do I have blood pressure, doctor?” You should never reply, “Well, you appear to be alive,” because doctors are in no position to be clever about such things. Most people who are on BP lowering drugs will never get any benefit from them and we have scant means of finding out who will. The only way to determine whether it is better to treat according to BP measured in the office, the home, or with an ambulatory monitor is by carefully constructed, very long-term interventional trials based on the three types of measurement. But then again, the more people you treat, the more cardiovascular events you will prevent: it’s just that the NNT/NNH ratio will become ever more unfavourable. This systematic review simply takes ABPM as the reference standard and compares this with office and home measurements. The latter tend to be higher: so is ABPM “better”? No, it is just lower.

Why do we prescribe non-steroidal anti-inflammatory drugs so freely? They burn holes in the upper GI tract, precipitate heart failure, and most of them increase myocardial infarction by the same amount as smoking. The trouble is that they work a bit, and patients and doctors simply haven’t many alternatives. As people get older, they take more NSAIDs and they get more atrial fibrillation. Are they by any chance related? Yes, says this Danish case-control study: the additional risk of AF is 40-70% in new users.

“QOF Must Be Abolished” is a slogan you will be familiar with if you are fortunate enough to receive e-mails from Chris Johnstone, a Scottish GP. Do you need persuading? Well, just read Tim Dornan’s paper here: as we already knew with diabetes, so it is with all these indicators – GPs were on a steady upward trend before 2004 but once QOF came in, performance slackened to match the top of the target range. Gaming between government and the BMA set in, and irrational new targets (e.g for HbA1c, “chronic renal disease” detection) were devised. By 2007, some detriment to non-QOF care was already detectable: how much more now? QOF must be abolished.

Plant of the Week: Allium cepa Aggregatum group

A couple of days ago we bought our first “purple scallions” in the tiny Farmer’s Market by New Haven Green. These resemble enormous spring onions and are wonderful in salads: they might be worthy of eating as a dish on their own, perhaps seethed in a little olive oil and dressed with balsamic vinegar. We shall try next week, when we buy some more. “Scallions” in modern New England are probably just the sprouts of the familiar European Allium cepa, grown huge since it was first brought here by the Pilgrim Fathers, who need not have bothered since America abounds in edible allium species.

The word “scallion” has died out in England and so we looked it up, thinking it must be of Norman French origin. How wrong we were. It is the same word as “shallot,” and both derive from the ancient Greek word askalonion. (Although this word, found in Theophrastus, ends in onion, the modern English word onion probably has an entirely different etymology.) Now askalonion bears a remarkable resemblance to the name of a Canaanite town, Askalon, now Ashkelon, one of the most ancient and fought-over of coastal settlements in human history. And the scallion is indeed named after this port, because it was from there that the Greeks traced the origin of the best onions.

Ashkelon has a long and often tragic history. Its remains date back to Neolithic times and it was successively occupied by Canaanites, Philistines, Israelites, Assyrians, Babylonians, Greeks, Phoenicians, Romans, Persians, Egyptians and even by Richard 1 of England on his Crusade, who built a castle on its ruins. The Mamluks finished the job, and under the Ottoman Turks it was just a poor village. In 1948 its 11,000 Palestinian residents were expelled and it is now an entirely Israeli city.

But the lasting resonance of the name Askelon comes from the Bible in David’s great lament for Saul and Jonathan in 2 Sam v 17-27. You will not need to chop scallions to weep over this passage, one of the greatest things in world literature:

17And David lamented with this lamentation over Saul and over Jonathan his son
   
 18(Also he bade them teach the children of Judah the use of the bow; behold, it is written in the Book of Jasher):
   
 19″The beauty of Israel is slain upon thy high places! How are the mighty fallen!
   
 20Tell it not in Gath, publish it not in the streets of Ashkelon, lest the daughters of the Philistines rejoice, lest the daughters of the uncircumcised triumph.
   
 21″Ye mountains of Gilboa, let there be no dew, neither let there be rain upon you, nor fields of offerings. For there the shield of the mighty is vilely cast away, the shield of Saul, as though he had not been anointed with oil.
   
 22″From the blood of the slain, from the fat of the mighty, the bow of Jonathan turned not back, and the sword of Saul returned not empty.
   
 23″Saul and Jonathan were lovely and pleasant in their lives, and in their death they were not divided; they were swifter than eagles, they were stronger than lions.
   
 24″Ye daughters of Israel, weep over Saul, who clothed you in scarlet, with other delights, who put on ornaments of gold upon your apparel.
   
 25″How are the mighty fallen in the midst of the battle! O Jonathan, thou was slain in thine high places.
   
 26I am distressed for thee, my brother Jonathan; very pleasant hast thou been unto me. Thy love to me was wonderful, passing the love of women.
   
 27″How are the mighty fallen, and the weapons of war perished!”

NEJM  30 June 2011  Vol 364
2483    The world of African emergency medicine is one which many noble British GPs have visited, but I alas am not of their number. I have merely braved the acute takes of celebrated New England hospital, where I learned yesterday that emergency departments throughout the world exhibit a hypotension-fluid bolus reflex. It is a sort of iatrogenic renin-angiotensin system: if blood pressure drops, the doctor immediately inserts fluid and sodium. Never mind if the patient is in renal or cardiac failure, in it goes. A similar procedure is routine in many hospitals looking after children with severe infection throughout the world. In the old days the doctor would bleed them: now we give them false blood in the form of regular bolus saline with or without albumin. Like bleeding for two thousand years, everyone knew this must be right, until somebody did this trial in several African hospitals and found that saline boluses increase mortality. See the editorial, “Fluid Resuscitation in Acute Illness — Time to Reappraise the Basics.”

2496   In real life, oncology is a gruelling specialty, where you discharge your successes early, and stay with your other patients until they are too desperately ill for you to do anything more. By contrast, the armchair oncologist lives in a world of optimism and success, as three papers in this week’s NEJM illustrate perfectly. I don’t suggest you actually read them: after all, genomics is best left to gene gnomes and chemo is definitely best left to people in protective clothing and facemasks. But it is great to see some old bastions of disease begin to crumble, even if we can’t understand all that is involved. For example, do you understand myelodysplasia? Of course not: nobody does. But it’s in a diffuse disease spectrum like this that genomics can really prove a help, allowing the characterization of different subtypes with different patterns of progression and prognosis. Don’t even try to remember them – just know that they’re known.

2507   The next stage is to use these genomic tumour characteristics to develop targeted therapy, and here some of the most exciting work seems to be going on in disseminated malignant melanoma, previous the inexorable killer of many young patients. Here the most common mutation is BRAF (BRAF V600E), found in 30 to 60% of melanomas. Venurafenib is a potent, orally available inhibitor of this BRAF variant and proved much better at preventing death and disease progression than dacarbazine in this trial. Whether it can achieve long-term remission, we don’t yet know: but we do know from a very recent trial of a similar agent that this is occasionally possible.

2517   Ipilimumab works on a different pathway altogether and is, as you can tell from its name, a monoclonal antibody. It blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), a negative regulator of T cells, in case you want to know. The fact is that it is inevitably less specific than venurafenib but nonetheless this trial (combined with dacarbazine v dacarbazine alone) shows once again that small increments of progress in cancer can build up to considerable therapeutic advances. If you really want to know the current state of play in this fast-moving game, see the editorial, “Been There, Not Done That — Melanoma in the Age of Molecular Therapy.”

Lancet  2 July 2011  Vol 378
31    The Lancet does this so well – inspires dozens of researchers to spend months in close confinement collating global data from hundreds of observational studies so that you can have a few interesting charts to look at between sets at Wimbledon. The subject here is trends in fasting blood glucose and diabetes since 1980, and for once Richard Horton does not accompany the paper with waffle about what governments around the world must do, etc, because he is too busy attacking Great Ormond Street Hospital in his printed blog  instead. At least that means we get a sensible editorial from Martin Tobias instead, warning of “paralysis by analysis”, because we all know pretty well what these charts are likely to show, and also that they are going to be exactly the same for blood sugar as for diabetes, by definition. The upward trend is lowest for highly developed countries, Japan and central Europe, and highest for populations highly evolved for periods of starvation – so supporting the “thrifty genotype” hypothesis. We know that some boatloads of Polynesians got lost in the Pacific a thousand years ago and only 13 made it to the Island of the Long White Cloud. Small wonder that many modern Maori are obese and diabetic, and that “Oceania” shows the fastest rise in the modern epidemic of type 2 diabetes.

41   When I first started writing these reviews 13 years ago, it didn’t take any special prescience to foretell the outpatient management of deep venous thrombosis based on D-dimer, rapid access ultrasound and long-acting heparin, though in fact it was quite a long time coming. So why not move on to the OP management of pulmonary embolism? The simple answer is because some people will die, and even though this may not be statistically significant, it ain’t half psychologically significant. A previous trial was stopped prematurely because this happened in the OP group and not in the inpatient group, and the same happened in this French-Swiss trial. The trial is declared a success for non-inferiority in low-risk patients, but I think it will take more than this to bring about a change of practice.

57   A really first-rate readable review of tuberculosis claims that its incidence world-wide is now the highest in history. I wonder if that can really be substantiated? Anyway, you’re not likely to find a more comprehensive or better illustrated an account of what we know about this slouchy old killer, the factors which make people susceptible to it, how to use modern diagnostic testing, or how we might address the still growing problem of multiple drug resistant TB and its even deadlier successor, XDR-TB. The authors rightly call TB (rather than pneumonia) “Captain of the men of Death” as per John Bunyan, who also knew a thing or two about the role of comorbidity:

“ATTEN. Pray of what disease did Mr. Badman die, for now I perceive we are come up to his death?
WISE. I cannot so properly say that he died of one disease, for there were many that had consented, and laid their heads together to bring him to his end. He was dropsical, he was consumptive, he was surfeited, was gouty, and, as some say, he had a tang of the pox in his bowels. Yet the captain of all these men of death that came against him to take him away, was the consumption, for it was that that brought him down to the grave.”

— John Bunyan The Life and Death of Mr Badman (1680).

86   Post-splenectomy and hyposplenic states may seem a somewhat unlikely topic to carry one’s attention through ten pages, but a skim-read of this review reveals a lot of interesting and practical information. Although I am somewhat widely read in the topic of coeliac disease, I was surprised to learn that it can cause hyposplenism in a considerable proportion of undiagnosed patients: so much so that I wonder if it wouldn’t be worth doing a postmortem study measuring endomysial antibody in all non-splenectomised patients dying of overwhelming sepsis due to encapsulated bacteria.

BMJ  2 July 2011 Vol 343 (although all refs are 342)

Podiatry has long been the butt of medical jokes, and even a distinguished past president of the RCGP in his earlier, funnier days described the main entry requirements to the profession as “anosmia and a sharp pair of scissors.” Admittedly that was before chiropody had morphed into the higher discipline of podiatry, now blessed with its own professors and doctorates and research papers in the BMJ. Enough of this badinage: anyone who can stop old people with foot pain having falls is worth his or her salt. These academic podiatrists from Australia have done just that, and validated a clutch of simple interventions that can easily be acted on.

Another kind of study it is easy to sniff at is the qualitative investigation of patients’ priorities for management. In fact this kind of study is going to be critical to drive the necessary transformation from health professional driven care to patient driven care. Women with lymphoedema due to breast cancer treatment are here followed up and tell us what they really experience and what they really want. More of this, please. 

Arch Intern Med  27 June 2011  Vol 171

1061    “The main function of insoluble fiber is to increase fecal bulk.” Normally that is about all I am prepared to concede on the subject of dietary fibre before proceeding to coarse jests about its similar effect on the medical literature. But every sceptic should conscientiously read anything which might change his views, and so I have spent just a few more minutes than usual reading this paper, Dietary Fiber Intake and Mortality in the NIH-AARP Diet and Health Study. In line with some other population studies using food diaries, it seems to show that men increase their life expectancy by eating dietary fibre (soluble as well as insoluble), and even claims to have adjusted for the obvious confounder of fruit and vegetable intake. I suppose that this will be used by the “healthy food” industry to add even more indigestible rubbish to their artificial products. Writing from the benighted USA, I renew my plea for everyone to eat only real food and eat only what they enjoy. That way you will enjoy living; and if you live a bit longer, regard it as a bonus. As for the bulk of your stools, pay no attention to it but read a good book instead. This is the sum of what I have to say about dietary fibre.

1082   What should we call heart failure which is not due to systolic dyfunction? The two candidate terms are diastolic heart failure and heart failure with preserved ejection fraction (HF-PEF) and of the two I prefer the latter, though I don’t think it captures the full nature of the syndrome. I gave up reading the specialist literature about ten years ago, at which time it was still considered a grave crime to mention anything of this kind in British cardiological circles: at that point I had persuaded myself that the syndrome is not merely due to impaired ventricular filling but also due to reflected pressure waves from stiffened capacitance arteries and impaired myocardial perfusion during diastole (which is when the coronary arteries actually fill). I may well be wrong, since I have never carried out a single echocardiogram, and people now seem agreed on how to measure diastolic filling and to grade dysfunction as mild, moderate or severe. This single center study shows that the prognosis of HF patients in the latter two categories is fully as bad as with the higher degrees of left systolic dysfunction.

1100   “Although seeding trials are not illegal, they are unethical.” This nice clear statement comes at the beginning of a detailed narrative study of such a trial, the Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS). The trial dates back 15 years to the time when gabapentin was a new drug and Parke-Davis (now part of Pfizer) created the trial so that doctors would titrate up doses as much as possible. I can say that freely because company documents showing this are in the public domain, thanks to subsequent litigation. The authors of this paper go through the seedy process step by step. Lots of seeding studies are still carried out by drug manufacturers, increasingly outside the USA and Western Europe: hundreds of individual doctors are paid to carry out unblinded “investigation” of newly licensed products on their patients. These “trials” are usually scientifically valueless and designed to promote the use of unnecessary expensive medication by health systems and individuals who cannot afford it. They are indeed unethical.

Plant of the Week: Prunus “Apriplum”

It’s strange how even the plants and fungi of a country take on national characteristics. The toadstools on the lawns of America are big and bright and stocky and abundant. American fruit and vegetables tend to be the same, and often taste superior to their watery, half-ripe English counterparts. But the fruit flown here from California tends to be excessively firm in texture and indifferent in taste. We haven’t yet found our way to local New England producers, of whom much might be expected.

I wouldn’t buy a California plum (though they are already on sale), but I did buy a few Apriplums the other day. It seems that this is one of many recent hybrids between the ancient apricot from the Near East (Prunus armenaica) and one of the infinite modern varieties of  Prunus domestica, the plum tree. Here is a perfect balance between the pulpiness of the apricot and the firmness of the modern American plum, with the sweetness of both, and a stone (or pit) that comes away of its own. An excellent fruit, which might very well be growable in southern England, or failing that, in France or Spain.

JAMA  22 June 2011  Vol 305
2525   Our understanding of the causes of the syndrome we label type 2 diabetes comes in dribs and drabs, and this study of the preventive effect of drugs given for rheumatoid arthritis or psoriasis on the incidence of diabetes counts as a drib; or perhaps a drab. The most protective drug seems to be hydroxychloroquinine, with a hazard ratio of 0.54, which may be due to direct action on the beta-cells; TNF-blockers also have a preventive effect (HR 0.62). Those searching for a drug to market for ‘pre-diabetes’ may find this exciting: for the rest of us, the answer is less likely to lie in toxic pharmacotherapy than in getting enough exercise, keeping reasonably slim and avoiding too much food with a high glycaemic index.

2532   Once people cross the magic threshold for diabetes by producing a fasting blood sample of 7mmol/L glucose or more, we try to prevent the risks of the condition by controlling blood pressure and glycaemia, knowing that this will do something to reduce adverse cardiovascular events. But what about the kidneys? We are told that diabetes is the leading cause of kidney failure in the developed world and that we should try to do better, which we interpret as giving more drugs. But the evidence base in favour of intensified BP or glucose-lowering treatment for renal protection is very poor, and overall we are not denting the problem at all, according to the latest data from NHANES III. The incidence of T2DM is increasing and the proportion developing renal failure is staying exactly the same in the USA. In fact as the proportion with albuminuria is falling a bit, the proportion with impaired creatinine clearance is rising a bit. Is albuminuria a surrogate of any value at all?

2540   Last week we learned that delays of 12 hours in transfer to emergency departments led to higher mortality in Californian patients with myocardial infarction. This study looks at something far more focussed: the effect of transfer times on patients with MI when they are shuttled from one hospital to another to undergo primary percutaneous intervention. We’re not looking at 12 hours here, but at a mean DIDO time of 68 minutes. This acronym does not refer to the abandoned Queen of Carthage from Virgil’s Aeneid Bk IV, but stands for Door-In,Door-Out. All transfer times over 30 minutes carry extra mortality, confirming that time equals myocardium, and that DIDO delay should be a cause for lament (I would suggest “When I am laid in earth”; set to Musick by Mr. Henry Purcell).

2556   Because “diabetes” is defined by a threshold level of fasting blood glucose, any drug that raises blood sugar causes “diabetes”. But do such drugs cause the progressive decline in beta-cell function and the increase in cardiovascular risk that we normally associate with type 2 diabetes?For example, thiazide diuretics raise blood sugar but reduce blood pressure, stroke, and heart failure. When you stop the thiazide, the blood sugar often returns to normal. It is now becoming clear that statins are associated with a small rise in “incident diabetes”, and this meta-analysis shows that it is dose-related. Still, the risk from a high dose of statin amounts to one in 500 to acquire the label “diabetes”, versus one in 155 to avoid a real cardiovascular event. It would be interesting to characterise further the outcomes of people developing “diabetes” while on high-dose statins. It is quite possible that many would have true progressive type 2 DM while others might remain static and perhaps revert to normoglycaemia if they stopped the statin. And in either case, it is events that matter, not labels.

NEJM  23 June 2011  Vol 364
2381   The primary prevention of anything should cause anxiety. If we go about it by screening, by immunisation, or by pharmacotherapy, the question is always the same – what is the cost and what is the harm?  As a result of this study, we could tell every woman over the age of 60 that by taking exemestane she would reduce her chance of getting breast cancer by 65%, with no evidence of long term harm or significant side-effects. Or we could tell her that she would have to take the drug for 3 years to stand a 1 in 94 chance of benefit, that we don’t really know the long-term effects, and that this would cost the NHS £100 per month. Both statements would be equally true.

2392    Tedious work, but somebody had to follow up 120,877 people for up to 20 years to help us understand what factors make Americans fatter by an average of 3.35lb every 4 years. I quote the increase in Imperial pounds because these are retained in the USA even in medical circles, and most readers probably remember that 1lb=0.45359237kg. Most readers will probably also remember that Sir Francis Drake first brought the potato to England, although he didn’t. These wonderful and various South American tubers are now the main dietary cause of obesity in the USA, according to this study. They are particularly delicious when deep-fried in oil – sorry, I meant to say pernicious, not delicious.  

2405    Now for some serious reflection on hepatitis C. If you can get access to the full text, begin on p.2429, and read through a typically thorough and informative NEJM clinical review of the topic, illustrated with a clinical vignette and artwork of psychedelic exuberance. Hep C, you will remember, is very common worldwide and leads to hepatic cirrhosis, fibrosis, and neoplasia in 15-30% of chronically infected people. In the UK we see it most commonly in intravenous drug users (45% are infected) and occasionally in people who had blood transfusions before 1992. Standard treatment with peginterferon and ribavirin produces mixed results – 52% of white patients and 28% of black show a response. But with the coming of boceprevir and telaprevir all this is set to change, so there is a nice upbeat air about this review and the two research papers. If your patient doesn’t want treatment now, relax: in a year or two even better drugs may come along. Meanwhile, the first study of telaprevir in treatment-naïve patients with chronic hep C shows a response rate of 69-75% in the two regimens tested against peginterferon-ribavirin alone, which here had a 44% response rate. This 26 week regimen is a major advance: as the review article states, ‘A sustained virologic response is associated with permanent cure in the vast majority of patients.’

2417   In a parallel trial of chronic Hep C patients who had failed to respond to standard treatment with peginterferon/ribavirin, or who had relapsed afterward, adding telaprevir showed even better success – up to 88% in one treatment arm. What a pleasant change from all those RCTs of lipid-lowering strategies which have to study huge atypical groups for many years to squeeze out some result of borderline statistical significance and no clinical relevance. Oops, I am running ahead of myself.

2439   More exuberant NEJM artwork alleviates the tedium of reading about n-3 fatty acids in cardiovascular disease. These pics are majorly groovy man, and worth sticking on the front of your exercise book. Sorry, I was just having an Austin Powers flashback moment. There is no other reason to wade through this account of feeble hypotheses and bad trials, except to note that you must eat as much fish as you can, up to the age when you would like to die suddenly. Because according to GISSI, fish oils do prevent sudden death. Perhaps on my 85th birthday I shall eat oysters, lobster, and turbot and then forswear fish forever, hoping to drop dead with a glass of champagne in my hand.

Lancet  25 June 2011  Vol 377
2181    I have grieved over the SHARP trial for many years. I first learnt of it from a friend who had just joined the Clinical Trials Support Unit at my home university of Oxford. I wondered that he should want to spend some of the best years of his life working on a trial that at very best could only yield results of borderline significance. I wondered that the unit, which has done so much good work in the past, should undertake a study designed to do no more than find a market niche for ezetimibe in patients whose cardiovascular risk is increased by chronic renal failure. Enough said: this study tells us nothing about ezetimibe except that it was safe for the duration of this study in this group of patients. The comparator should clearly have been a more powerful statin, anyone’s natural choice when simvastatin fails to produce enough LDL-C lowering. In real life it would be SHARP practice to use expensive, unproven ezetimibe instead.

2193   From time to time I have sat watching modern youths playing endless computer games in which they arm themselves with various kinds of ammunition and rescue a damsel in distress from the clutches of a Nazi/Soviet/Al Qaida unit hidden in a building with lots of stairs and doors and booby traps. At least that is what I think was going on: I usually doze off early on. I think the people who write the programmes for these games also design stent trials, because whenever I wake up in the middle of reading one, the sensation is exactly the same. Is bivalirudin hiding behind that pile of wood? Is that a paclitaxel-eluting stent that just went into the Tora Bora cave complex followed by an evil man in a turban? Where are the Gestapo hiding sirolimus? Do I really care? Gosh, it can’t be that time already.

BMJ  25 June 2011  Vol 342
Another area of permanent warfare in cardiology is the use of anti-platelet agents. A huge market awaits the pharma company which develops a drug which is better than aspirin, or at least that is better than clopidogrel. In the past I have called this the Quest for the Holy Grel, and readers who like this kind of thing can also feast themselves on a therapeutics article comparing clopidogrel and prasugrel; whereas in the PLATO study the competing grel was ticagrelor. The BMJ doesn’t often publish subgroup spin-offs of trials like this, especially not any which could conceivably be thought of as promotional: but if ticagrelor really is superior to clopidogrel in patients selected for non-invasive management of acute coronary events, then it is perfectly legitimate to point this out. Astra-Zeneca, who paid for the trial, are hardly likely to see this as a huge market opportunity. As for the Greek philosopher who gave his name to this trial, I am sure he would want to encourage a Symposium on the whole subject of antiplatelet agents and the non-invasive management of STEMI, preferably with the traditional accompaniments of wine, fish and flute-girls.

High risk prescribing in primary care patients particularly vulnerable to adverse drug events – get squirming, because we GPs are all guilty. This Scottish study is worthy but unnecessarily dull because it does not tabulate its data. And of course it cannot cover the entire range of our malfeances. Many more studies are needed – my favourite would be a survey of co-prescription of drugs causing serotonergic toxicity. I hardly do a single session out-of-hours without seeing a patient who is taking a serotonin reuptake inhibitor alongside a contra-indicated drug such as tramadol, trazodone, or a tricyclic antidepressant. No wonder so many of them are jittery.

Ann Intern Med  20 June 2011  Vol 154
781    A great deal of the clinical decision-making we do is dependent on accurate measurement of the blood pressure. I spent a few years trying to deduce what this actually meant from the literature as it stood in the mid-1990s, and concluded that we scarcely knew what we were doing. We were given an ambulatory BP monitor for use in a research project, which we held onto and used for many years. But the literature about ABPM versus office readings was confusing then and is not much better now. On the other hand, a single office reading is never good enough to warrant a change in treatment, even if a QOF reminder desperately urges us to make one. This study makes the case for home readings as standard procedure. And the accompanying editorial makes a powerful case for a complete overhaul in our sloppy standards of BP measurement.

798   Last week’s excellent review of appendicitis in the BMJ made little mention of multidetector CT scanning as a diagnostic tool, which rather reassured me as I find the doses of radiation involved in this procedure quite alarming. Unfortunately it is a good diagnostic procedure, as this single-centre prospective US cohort study demonstrates. The temptation will be to do CTs on every adult coming in with suspected appendicitis, for medicolegal reasons if not clinical. If this happens, I think we might need a tattoo to accompany each CT so that nobody is exposed to more than say 3 Sv in a lifetime. (A little test: explain the relation between rads, rems, Grays and Sieverts).

Fungus of the Week: Stropharia rugosoannulata

A fungus already? I’m afraid so, as I write from New England where they are coming up in abundance after days of thunderstorms. Most of them are amanitas and russulas of dubious edibility, but this stropharia is a prized esculent and is even grown commercially. So I was very pleased indeed when I found one this afternoon, and I have just eaten it on your behalf and can pronounce that it meets expectation. I must now hasten to complete the links and send out these reviews before I succumb. All British stropharia species are small and poisonous, by the way.

I should really be telling you all about the wonders of New England trees and shrubs, forests of oak and maple with an understory of sassafras and sumachs: but these must wait for another time. There are plenty of plants to enjoy in Old England at this time of year, and English gardens are much more richly stocked than most American ones, especially with good roses. But the fungi in eastern America surpass expectation.

JAMA  15 June 2011  Vol 305
2419    Here is a study which may have major resource implications for you and your commissioning group, because it seems to show that there is no mortality benefit over 6.7 years in men who undergo bariatric surgery. You can relax: there will be no need to find money to pay Barry the surgeon after all. But this appears to conflict with previous observational evidence, and there are plenty of unanswered questions about high-risk subgroups, particularly diabetic patients. So you had better pay close attention to this paper, and that is no easy task: essentially you are being asked to examine various methods of matching and comparison. Simply eyeballing the characteristics of the 850 surgical cases and the 41 244 controls, there are major differences in age and BMI, but these were then eliminated by one-to-one propensity matching. Let me direct you to the summary: “In unadjusted Cox regression, bariatric surgery was associated with reduced mortality (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.51-0.80). After covariate adjustment, bariatric surgery remained associated with reduced mortality (HR, 0.80; 95% CI, 0.63-0.995). In analysis of 1694 propensity-matched patients, bariatric surgery was no longer significantly associated with reduced mortality in unadjusted (HR, 0.83; 95% CI, 0.61-1.14) and time-adjusted (HR,0.94; 95% CI, 0.64-1.39) Cox regressions.” Go on – after reading it a few times, you will understand. At least I think you will, but you can imagine how terrifying it is for a superannuated Brit GP to try and look savvy in a room full of super-bright young Americans who get this sort of stuff immediately and then move straight on to Bonferroni corrections and chi-squared testing.

2440    Now here is the kind of outcomes research even I can understand: patient has myocardial infarction, local emergency department is on divert so ambulance is diverted, twelve hours are lost. This is in California, a big state, but it’s still hard to credit a 12-hour delay – and does it matter? It sure does. These MI patients are more likely to be dead at 30 days, 90 days, 9-months and one year.

NEJM  16 June 2011  Vol 364
2282    The chief conceptual triumphs of preventive medicine date back to the nineteenth century, the age of public sanitation and vaccination. Both are still needed in the twenty-first century if the mortality from rotavirus gastroenteritis in infants and children is going to be reduced in developing countries. The countries in question here are Mexico and Brazil, which have introduced a policy of universal vaccination with the monovalent vaccine RV1. The aim of the study was to determine whether this vaccine carries a significant risk of causing intussusception and how this might compare with the mortality reduction from rotavirus infection. As expected, the temporal association of the new vaccine with intussusception is much smaller than with its predecessor Rotashield, and the arithmetic approximates to one death from the complications of intussusception for every 250 rotavirus deaths prevented.

2293    Every 10-12 years, a belt of Africa from Ethiopia to Senegal is struck by an epidemic of group A meningococcal disease – one of those oddities that bacteriologists like to tell us about, and which we ought by now to have brought under control. If all goes to plan, that may be what this vaccine study presages. A new MenA conjugate vaccine PSa-TT was tested on babies and on individuals between 2-29 years of age, and showed better immunogenicity than a previous quadrivalent polysaccharide vaccine. There is good reason to believe that the new vaccine, unlike the old, will produce a durable response and will reduce carriage – if given on a whole-population scale, as envisaged by Bill and Melinda Gates.

Lancet  18 June 2011  Vol 377
There isn’t much to engage the generalist in the research published in The Lancet this week – not even much occasion for scorn or indignation. A rather weak Australian study finds a 38% reduction in CIN-1 cervical lesions following a HPV vaccine programme, which the Abstract announces as a 0.38% reduction. A global survey of health in adolescence and young adulthood provides a mass of largely unsurprising data. A trial of novel chemotherapy for colorectal cancer proves negative.

But The Lancet announces that it will be running a new kind of Clinical Series from this week onwards, promising to explain the latest findings from basic research and at the same time provide a practical guide for the clinician. We begin with Arthritis:

2115   Osteoarthritis: an update with relevance for clinical practice delivers what it promises. The problem is that our knowledge of osteoarthritis hasn’t advanced greatly, and I was hard put to find any new learning points in this review, worthy and comprehensive though it is.

2127   The next article also combines French and Dutch authorship but is a very different beast. The purported subject is Spondyloarthritis, described as “a group of several related but phenotypically distinct disorders: psoriatic arthritis, arthritis related to inflammatory bowel disease, reactive arthritis, a subgroup of juvenile idiopathic arthritis, and ankylosing spondylitis (the prototypic and best studied subtype).” I was looking forward to enlightenment about this perplexing group of related diseases associated with theHLA-B27 tissue type, but practically the whole of the article refers exclusively to AS. The cellular mechanisms section settles on interleukin-23 as a potential therapeutic target, beyond tumour necrosis factor α. In fact I’ve now read so many of these papers that I can almost understand when they say that “TNF would simultaneously drive destruction and inhibit remodelling by the Wnt pathway by upregulating Dickkopf-related protein 1.” You too can reach this level of enlightenment if you read this article, but I don’t think you will find much here to help you identify and treat spondyloarthritis amidst the endless procession of joint aches you see every day.

2138   And so to the third article, dealing with juvenile idiopathic arthritis. There is a big overlap with the subject of the previous paper, because as the authors remark, “enthesitis-related arthritis is a form of undifferentiated spondyloarthropathy.” I have no idea what that might mean, but most of the sufferers are HLA-B27 positive and many go on to develop sacro-iliitis. However, the emphases in this account are quite different: the interleukins of interest are 1,6 and 18, and the disease marker of promise is ANA for diagnosis, and myeloid-related proteins 8 and 14 for disease response. If you really want to swank in rheumatological company you can also slip in the odd reference to FOXP3-positive Tregs.

BMJ  18 June 2011  Vol 342
Here is the latest study to make one wonder whether we aren’t doing more harm than good for many of our patients with chronic obstructive pulmonary disease. It’s a meta-analysis of the randomised controlled trials of a tiotropium mist inhaler which shows a 52% increase in mortality from the use of this anticholinergic in this form. Admittedly the absolute NNK (number needed to kill) for one year is 124; but given such clear evidence of harm, how did this stuff get licensed? By showing symptomatic benefit and a reduction of exacerbations, it seems. And how do bronchodilators kill people with COPD? The editorial speculates that it’s by helping cigarette smoke to penetrate the small airways more effectively – a hypothesis which should be testable.

For many years, I tried to ban discussion of wart treatment at our regular practice nurse/doctor meetings, but invariably someone would whisper “I know we’re not supposed to discuss warts, but…” and it would all start again. People like me who recommended salicylic acid application or no treatment would argue with others who felt we owed our patients a duty of wart care involving a supply chain for liquid nitrogen on certain days of the month. Now here should be an end to the debate. In this randomised trial, one is no better than the other. But even now, from my former practice, I can hear a soft murmur of dissent. As Henry Kissinger once said of academe, “The arguments are so fierce because the stakes are so low.”

I am completely baffled as to why anyone would want to carry out a case-control study of the association between (recollected) maternal sleep practices and late stillbirth, still more why any journal should want it to see the light of day. Is somebody proposing that high-risk women should sleep in a particular way? Or that mothers bereft in this way should feel to blame for lying awake on their left sides? Or that people can recollect their position while asleep? Bizarre.

However, just to drive home my point about the general quality of the BMJ’s Clinical Reviews, here’s an excellent practical account of the diagnosis and management of ectopic pregnancy.

Arch Intern Med  13 Jun 2011  Vol 171
977    Non-invasive cardiovascular imaging sounds good. This meta-analysis tries to determine whether it has any place in the primary prevention of CV disease. To my mind, the review casts the net much too wide. Coronary CT angiography, coronary calcium scoring, and radionuclide angiography all involve large doses of ionizing radiation: even if they had any demonstrable benefit in asymptomatic individuals, their advertisement to the general public would seem inadvisable. Nobody should have more than a couple of these tests in a lifetime if they can avoid it. As they have no demonstrable benefit, I think their promotion is unethical. The direct harm of exercise ECG and arterial ultrasonography, however, lies more in the inaccuracy of the tests and their likelihood of generating nothing but anxiety or false reassurance. And yet people love these awful screening procedures and attribute nothing but good to them, even when the harm in unnecessary intervention is extreme, as Lisa Schwartz and Steve Woloshin have nicely demonstrated.

998   Now one form of overdiagnosis that has become very popular is osteopenia leading to the prescription of bisphosphonates. These drugs in turn often cause oesophagitis or gastric irritation, and so countless old ladies dutifully take proton pump inhibitors every morning and a long-acting bisphosphonate on Sundays. Here is a Danish database study looking at how the use of a PPI might affect the rate of hip fracture in patients taking alendronate. It seems to show a dose-related decrease in the protection afforded by the alendronate: this needs confirmation from say the UK GPRD, but if true will need a whole new approach to bisphosphonate prescribing – yearly IV zolendronate for everyone, perhaps?

Plant of the Week: Taxodium distichum “Falling Waters”

The swamp cedar comes from the southwest USA but flourishes throughout the temperate world. The standard form grows to 30m and more and is widely planted in botanical gardens next to Metasequoia glyptostroboides, the dawn redwood, as a test for would-be tree experts. The taxodium has slightly finer, paler leaf-needles.

If you have a grand garden with a lake you should plant your mighty taxodium by the waterside or even in the water, as at the botanical garden of Cracow university. There it may reward you by forming large “knees” of root rising above the water. But if you possess merely a humble, dry little garden you may still grow this excellent tree and enjoy its autumn colour and ferny spring awakening. In the USA, and perhaps in the UK too, there is now a weeping form which won’t grow much above 5m. In the botanic garden at Smith College, Mass, they have a couple of these grown into a pergola – very nice too.

JAMA  8 June 2011  Vol 305
2295    Ovarian cancer almost always presents too late for a cure, so screening asymptomatic women must offer our best chance of reducing its high mortality. In this ground breaking study, 78 216 women were randomised to usual care or to have CA-125 measurements every year for 6 years and transvaginal ultrasound every year for 4 years. Here are the follow-up figures 10-13 years later. In the screened group, the detection rate for ovarian cancer (212 cases) was higher, but failed to reach statistical significance. There were 3285 false positive results – 15 for every true positive – and over one thousand women underwent unnecessary surgery, of whom 163 experienced at least one serious complication. And the effect on ovarian cancer mortality? A tiny bit higher in the screened group.

2312    The conquest of many childhood cancers is one of the success stories of postwar medicine, showing that the fine-tuning of highly toxic treatment regimens can sometimes lead to dramatic rates of cure. But always at a price. The British Childhood Cancer Study looks at the late cost in terms of new cancers after 25 years. There is a fourfold increase of risk, concentrated on gastrointestinal and genitourinary tumours, most of which seems to be attributable to abdominal irradiation for lymphoma or Wilms tumours. The authors argue that adults who have survived such treatment should have regular colonoscopy because of their increased risk of colorectal cancer.

2320    You’ll have gathered by now that this issue of JAMA is devoted to cancer. Now I am writing from the USA, where it is a known fact that every British GP has sat on a Death Panel and gleefully withheld life prolonging treatment to the pleading, wasted cancer patients who queue up at the barred gates of his socialist health facility. That aside, there’s some pretty good debate over here about the unaffordability of many new cancer drugs, such as sipuleucel for advanced prostate cancer (see p.2347). One way to overcome this might be to try out orphan drugs – compounds off patent, with known pharmacological actions but no clear uses – in trials on cancer patients. Alas, this study shows that the incentives offered to pharmaceutical companies to do this have resulted in a rash of badly conducted, nonrandomised, often open-label, trials: exactly the sort we need least in life-threatening disease.

2327   Now there’s no clearer sign that you’re on to something in medicine than when people who ought to be dead remain alive. That’s the exciting aspect of this trial of imatinib in advanced malignant melanoma. OK, this was a small open-label study (n=28) of a highly selected subgroup with mutations of the tyrosine kinase receptor KIT. Twenty-four of them are now dead. But two are showing long-term control and two are in complete remission. And it seems that their response fits the genomics of their tumours: not a great step forward, so far – but a definite step.

NEJM  9 June 2011  Vol 364
2187   Poorly old people with aortic stenosis can decompensate and die if you don’t do something at the right time, or else they can die on the table if you do. The middle way between fatal inactivity and fatal open valve replacement is transcatheter valve replacement, which has been shown to be effective for those definitely too unwell to have a thoracotomy. This trial attempts to assess the risks and benefits of those half way to being too poorly – and ends up with a complex balance of benefits and risks. An open op may kill you sooner if you’re unlucky, but survival at one year is the same with the two procedures; on the other hand, you are slightly more likely to get a stroke or a peripheral artery complication with the closed procedure. I don’t envy those who have to make these decisions – patients as well as doctors.

2208   “The 6-month rate of expulsion of an IUD after immediate insertion was higher than but not inferior to that after delayed insertion.” Now the editors of this august journal deserve my gratitude for publishing a letter with my name under it, on the very day I landed in New England (it’s really John Yudkin’s letter, of course); but honestly, what sort of sense does this sentence make? The IUD referred to is not intrauterine death but an intrauterine contraceptive device, or IUCD, and this “higher than but not inferior to” gobbledegook refers to a pre-set “non-inferiority” definition of >8% IUCD expulsion. The IUCDs in question were fitted at the time of first trimester abortion as opposed to 2-6 weeks later, and the study shows that by fitting IUCDs there and then, you get higher take-up rates but lose a few to early expulsion. That over-compressed sentence I quoted is very confusing and unnecessary: the NEJM editors have excellent taste in correspondence, but they do need someone to check their English; and I am ready and waiting and a mere two hours’ drive from Boston.

2235   It’s time for the sirtuins. This article promises to help you understand “ the biology that undergirds their promise as therapeutic targets.” Undergirds: with such delicious words plucked from the dictionary, maybe the NEJM doesn’t need my help after all. And here is the full magnificence of  NEJM artwork too, with lots of arrows doing very busy things inside mitochondria, and a text guaranteed to baffle all but the most diligent. So what are sirtuins then? Well, thingies that tend to make you burn up and die, and so the agents of ageing, perhaps. If you live long enough, you may one day find out.

Lancet  11 June 2011  Vol 377
2007   Anyone working in our profession must be appalled at the level of intelligence shown by the British schoolgirl. If they got any brighter there would be no male doctors at all. It is a matter of universal lament that there is hardly a single female medical school applicant who doesn’t have 5 top grade A-levels plus grade 8 in oboe and a track event record, never minding the fact that most have halved the infant mortality of a South African township or two in their gap year. Now here is a study suggesting that we need to give them more iodine to improve their IQs, urgently. If this is deficiency, Lord preserve us from sufficiency.

2013   Terutroban was an antiplatelet agent. So is aspirin. Servier did a big RCT hoping to show that terutroban might be better for the secondary prevention of cardiovascular events following stroke or TIA. It was not and the study was stopped early for futility; so goodbye terutroban.

2023   Doctors faced with sick patients often reach for a handful of steroids, but it’s often difficult to know whether they do good or harm. In this Dutch study, patients admitted with uncomplicated community-acquired pneumonia were randomised to receive intravenous dexamethasone or saline. The steroid-treated group left hospital a day sooner on average.

BMJ  11 June 2011  Vol 344
How long is a course of anticoagulation? Where I practised, it was either six months or indefinitely. Here is an analysis of individual participant data from 7 trials in venous thromboembolism which suggests that the answer may be three months in the case of events with a clear precipitant and indefinitely in the case of unprovoked VTE.

The primary care department at Oxford University has tolerated my presence for many years, though I have never been in a position to contribute much to its formidable record of important publications. Here is an exemplary attempt to examine the diagnostic value of laboratory tests in identifying serious infection in febrile children by a meta-analysis of seven studies. You will learn a lot about the difficult task of meta-analysing diagnostic studies if you read this paper slowly and in full – for example “It is easiest for clinicians to think of a positive result with a likelihood ratio of 2 as making it twice as likely that the patient has the disease. However, this is imprecise as the likelihood ratio applies to the change in odds rather than probability of disease— that is, the likelihood ratio×pre-test odds=post-test odds. So to calculate the precise impact of the test result on disease probability, it is necessary first to convert the pre-test probability to odds (pre-test odds=pre-test probability/(1−pre-test probability)) and then after multiplying by the likelihood ratio convert the odds back to probability (post-test probability=post-test odds/(1+post-test odds)).” David Mant, who oversaw this study, once spent time trying to explain this to me – probably the worst 20 minutes of his life. It is terribly important, but not the stuff of busy sessions full of sick kids. And there remains the stubborn fact that these studies tell us the odds which apply to hospital departments, not the places we may happen to be. So is there a take-home message? Well, forget about the white count. A very high CRP spells trouble – like you didn’t know. Procalcitonin? Probably good, but not available. More primary care studies are needed, as they say: and now it’s the new prof’s turn.

Ann Intern Med  7 June 2011  Vol 154
709    The Bayesian world of acute primary care is populated by people we half know, who have illnesses that we half diagnose, in periods that are half stress and half boredom, accompanied by cups of tea and unwholesome confectionery. Amongst the earaches and the babies who vomit at unfortunate moments, there is quite likely to be a young lady taking oral contraception who has stabbing chest pain and feels generally off. You get her to press on the spot and she says ouch. Is this a sufficient diagnostic test? What if she has a slight fever? Am I compiling a Wells score? Should I do a D-dimer? Frankly I have no idea, so I suppose I better had. The orderly Dutch, who do things so much more thoroughly, should be our guide in such matters: here they compare the performance of four clinical decision rules in combination with D-dimer “in the diagnostic management of acute pulmonary embolism”, according to the title. I don’t know why they put it in this clumsy fashion: what they mean is to safely rule out PE. All the decision rules they look at – Wells rule, revised Geneva score, simplified Wells rule, and simplified revised Geneva score – are equally good rule-outs when combined with D-dimer in hospital emergency departments.

719    It’s called original research, but it’s not as if you really needed a new cohort study to tell you that women smokers get peripheral vascular disease. Still, a useful reminder that treatments for nicotine addiction are amongst the most useful interventions you ever prescribe: far more beneficial than most of the statins and antihypertensives you spend your day handing out to healthy people.

752    So how do our British death panels actually work? I’m going to keep this excellent account of NICE and its modi operandi on my memory stick, because I intend to sell my expertise to the Sarah Palin nomination campaign when it meets in New Hampshire in September. And also the next one on p.756 on cost-effectiveness as assessed by our much admired national body, even though it has now been stripped of its direct rationing powers. 

Plant of the Week: Fagus sylvatica “Pendula”

This is a traditionally a tree for large spaces and wide vistas, such as country parks. But the scale of buildings in the science area of Yale, where we currently live, is such that you can quite comfortably fit a weeping beech tree between them and let it grow to impressive American arboreal standards. Like elephants, these trees manage to be both massive and homely. Moreover they have splendid grey bark, and well, yes, they also have trunks.